The Tissue Nonspecific Alkaline Phosphatase
Gene Mutations Database

Welcome to the ALPL gene mutations database. This site has been compiled to provide up-to-date information about genetic variation of the ALPL gene responsible for hypophosphatasia.

The database has been initiated by the SESEP Laboratory (now integrated in Versailles Hospital as the Unit of Constitutional Genetics) and the Unit of Cell and Genetics Pathology (EA2493) of the University of Versailles-Saint Quentin en Yvelines, France.


The database

Editor : Etienne MORNET Ph.D.
Last update : May 31, 2016
Total number of mutations described : 317



Hypophosphatasia (MIM 146300, 241500, 241510)

Hypophosphatasia is a rare inherited disorder characterized by defective bone and teeth mineralization and deficiency of serum and bone alkaline phosphatase activity. For severe forms, the prevalence of the disease has been estimated to 1/300,000 in Europe and 1/100 000 in Canada. The symptoms are highly variable in their clinical expression, which ranges from stillbirth without mineralized bone to early loss of tooth without bone symptoms (Whyte 1994). The transmission of severe forms is autosomal recessive while milder forms may be transmitted as dominant or recessive autosomal traits. The disease is due to mutations in the alkaline phosphatase liver-type (ALPL) gene, also named the TNSALP gene. See more informations in Orphanet.

The ALPL gene (ID:249; MIM 171760), localized on chromosome 1p36-34 (Greenberg et al. 1990), consists of 12 exons distributed over 50 kb (Weiss et al. 1988) and is subject to very strong allelic heterogeneity. To date, at least 317 distinct mutations are known (see the list of mutations below and the list of polymorphisms). The patients examined mostly consisted of European, North-American, Australian and Japanese individuals.

Table of mutations

Exon 1 | Exon 2 | Exon 3 | Exon 4 | Exon 5 | Exon 6 | Exon 7 | Exon 8 | Exon 9 | Exon 10 | Exon 11 | Exon 12 | Large deletions | Polymorphisms

Exon Base change
Amino acid change

Reference
Clinical form of the patient Genotype of the patient


Residual activity

Dominant negative effect
Conservation
Standardized nomenclature
Non standardized nomenclature
%
WT
reference
% 50/50
reference
1 c.-195C>T     Taillandier et al. 2000 perinatal c.-195C>T/p.Cys201Tyr         na
2 c.3G>A p.Met1Ile Met-17Ile Mentrup et al. 2011 adult p.Met1Ile/? 1.0 Mentrup et al. 2011 59.0 Mentrup et al. 2011 ++
2 c.17T>A p.Leu6Ter Leu-12Ter Taillandier et al. 2000 childhood p.Leu6Ter/?         na
2 c.41T>C p.Leu14Pro Leu-4Pro Versailles lab Jul 2010 adult p.Leu14Pro/p.Glu191Lys         +
2 c.43_46delACTA p.Asn16ProfsX2   Versailles lab March 2011 infantile c.43_46delACTA/p.Arg220Gln         na
2 c.50C> T p.Ser17Phe Ser-1Phe Mornet et al. 1998 infantile p.Ser17Phe/p.Gly75Ser 19.0 Zurutuza et al. 1999     +
2 c.61G>A p.Glu21Lys Glu4Lys Research center for medical genetics, Moscow, Apr. 2015 adult p.Glu21Lys/?         ++
IVS2 c.62-1G>C     Versailles lab March 2013 perinatal c.62-1G>C/c.62-1G>C         na
3 c.69_74delGAAAGA     Versailles lab May 2012 perinatal c.69_74delGAAAGA/p.Asn49Ile         na
3 c.82T>G p.Tyr28Asp Tyr11Asp Yang et al. 2013 odonto p.Tyr28Asp/p.Tyr388His 0 Yang et al. 2013

45

Yang et al. 2013 ++
3 c.83A>G p.Tyr28Cys Tyr11Cys Taillandier et al. 2001 infantile p.Tyr28Cys/p.Arg136His 7.2 Taillandier et al. 2001     ++
3 c.88C>T p.Arg30Ter Arg13Ter Versailles lab Dec 2010 perinatal p.Arg30Ter/p.Gly129Arg         na
3 c.94C>T p.Gln32Ter Gln15Ter Versailles lab. Apr 2011 perinatal p.Gln32Ter/c.648+1G>A         na
3 c.98C>T p.Ala33Val Ala16Val Henthorn et al. 1992 childhood p.Ala33Val/p.Tyr436His         +
3 c.106A>C p.Thr36Pro Thr19Pro Versailles lab Nov 2008 perinatal p.Thr36Pro/p.Thr36Pro         ++
3 c.110T>C p.Leu37Pro Leu20Pro Versailles lab oct. 2003 perinatal p.Leu37Pro/p.Leu37Pro         ++
3 c.119C>T p.Ala40Val Ala23Val Mornet et al. 1998 perinatal p.Ala40Val/p.Gly473Ser 2.3 Zurutuza et al. 1999 51.3 Lia-Baldini et al. 2001 +
3 c.129delT p.Gln44ArgfsX23   Whyte et al. 2015 childhood c.129delT/p.Tyr436Cys         na
3 c.130C>T p.Gln44Ter Gln27Ter Mornet E, unpublished perinatal p.Gln44Ter/c.662insG         na
3 c.146A>T p.Asn49Ile Asn32Ile Versailles lab May 2012 perinatal p.Asn49Ile/c.69_74delGAAAGA         +
3 c.151G>T p.Ala51Ser Ala34Ser Mumm et al. 2002 infantile p.Ala51Ser/p.Thr134His         ++
3 c.152C>T p.Ala51Val Ala34Val Taillandier et al. 2001 infantile p.Ala51Val/p.Val459Met         ++
3 c.180T>C p.Asp60Glu Asp43Glu Whyte et al. 2015 childhood p.Asp60Glu/N         ++
IVS3 c.182-2A>C     Whyte et al. 2015 childhood c.182-2A>C         na
4 c.184A>T p.Met62Leu Met45Leu Taillandier et al. 1999 infantile p.Met62Leu/c.1172delC 27.4 Zurutuza et al. 1999     ++
4 c.184A>G p.Met62Val Met45Val Spentchian et al. 2003 infantile p.Met62Val/p.Met62Val         ++
4 c.186G>C p.Met62Ile Met45Ile Taillandier et al.2005 childhood p.Met62Ile/p.Glu191Lys 0 Taillandier et al.2005     ++
4 c.187G>C p.Gly63Arg Gly46Arg Spentchian et al. 2003 infantile p.Gly63Arg/p.Gly63Arg         ++
4 c.187_205del19 p.Gly63LeufsX53   Versailles lab Jan 2010 adult c.187_205del/?         na
4 c.188_205dup18 p.Gly63_Thr68dup   Guanabens et al. 2013 adult c.188_205dup18/?         na
4 c.188G>T p.Gly63Val Gly46Val Lia-Baldini et al. 2001 infantile p.Gly63Val/N 0.8 Lia-Baldini et al. 2001 26.0 Lia-Baldini et al. 2001 ++
4 c.203C>T p.Thr68Met Thr51Met Orimo et al. 2002 childhood p.Thr68Met/p.Ala177Thr 5.2 Orimo et al. 2001     ++
4 c.211C>T p.Arg71Cys Arg54Cys Henthorn et al. 1992 infantile p.Arg71Cys/p.Asp294Ala 0 Fukushi-Irié et al. 2000 35.0 Fauvert et al. 2009 ++
4 c.211C>G p.Arg71Gly Arg54Gly Research center for medical genetics, Moscow, June 2015 adult p.Arg71Gly/?         ++
4 c.211C>A p.Arg71Ser Arg54Ser Orimo et al. 2002 childhood p.Arg71Ser/? 2.9 Orimo et al. 2001     ++
4 c.212G>C p.Arg71Pro Arg54Pro Henthorn et al. 1992 perinatal p.Arg71Pro/p.Gln207Pro         ++
4 c.212G>A p.Arg71His Arg54His Taillandier et al. 2001 perinatal p.Ala40Val/p.Arg71His 1.0 Fauvert et al. 2009 30.5 Fauvert et al. 2009 ++
4 c.215T>C p.Ile72Thr Ile55Thr Versailles lab oct. 2004 odonto p.Ile72Thr/N 5.1 Fauvert et al. 2009 40.2 Fauvert et al. 2009 ++
4 c.216A>G p.Ile72Val Ile55Val Versailles lab dec. 2014 infantile p.Ile72Val/p.Ile72Val         ++
4 c.217_219delCTC p.Leu73del Leu56del Versailles lab aug. 2013 asymptomatic* p.Leu73del/N         na
4 c.223G>A p.Gly75Ser Gly58Ser Mornet et al. 1998 infantile p.Ser17Phe/p.Gly75Ser 3.5 Zurutuza et al. 1999     ++
4 c.227A>G p.Gln76Arg Gln59Arg Mornet et al. 2001 infantile p.Gln76Arg/p.Thr134Asn         ++
4 c.242delC p.Pro81LeufsX41 Pro64LeufsX41 Versailles lab Jul 2009 perinatal c.242delC/c.242delC         na
4 c.247G>T p.Glu83Ter Glu66Ter Versailles lab Apr 2011 infantile p.Glu83Ter/p.Glu83Ter         na
4 c.251A>T p.Glu84Val Glu67Val Wei et al. 2010 odonto p.Glu84Val/N         +
4 c.262G>A p.Glu88Lys Glu71Lys Mohn et al. 2011 infantile p.Glu88Lys/p.Pro307Leu         ++
4 c.277C>T p.Pro93Ser Pro76Ser Peach et al. 2007 prenat. benign p.Pro93Ser/p.Thr134His         ++
IVS4 c.297+3G>T     Versailles lab. Jan 2011 infantile c.297+3G>T/p.Thr100Met         na
IVS4 c.298-2A>G     Taillandier et al. 2000 perinatal c.298-2A>G/c.997+3A>C         na
IVS4 c.298-1G>A     Zhang et al. 2012 adult c.298-1G>A/c.298-1G>A         na
5 c.299C>T p.Thr100Met Thr83Met Mornet et al. 2001 infantile p.Thr100Met/p.Glu191Lys 1.3 Fauvert et al. 2009 28.2 Fauvert et al. 2009 ++
5 c.301T>G p.Tyr101Asp Tyr84Asp Versailles lab. Feb 2012 odonto p.Tyr101Asp/N         ++
5 c.303_311del p.Asn102_Asn104del Asn85_Asn87del Versailles lab Jul 2007 perinatal c.303_311del/p.Gly491Arg         na
5 c.318G>C p.Gln106His Gln89His Balasubramaniam et al. 2010 infantile p.Gln106His/p.Gln106His         ++
5 c.323C>T p.Pro108Leu Pro91Leu Herasse et al. 2003 odonto p.Pro108Leu/N 1.9 Fauvert et al. 2009 24.0 Fauvert et al. 2009 ++
5 c.331G>A p.Ala111Thr Ala94Thr Goseki-Sone et al. 1998 odonto p.Ala111Thr/? 2.0 Fauvert et al. 2009 48.7 Fauvert et al. 2009 ++
5 c.334G>A p.Gly112Ser Gly95Ser Witters et al. 2004 infantile p.Gly112Ser/p.Arg391Cys         ++
5 c.334G>C p.Gly112Arg Gly95Arg Whyte et al. 2015 odonto. p.Gly112Arg/N         ++
5 c.335_340dupGCACCG p.Gly112_113dup Gly95_96dup Wenkert et al. 2011 prenatal benign G95_96dup/p.Glu191Lys         na
5 c.340G>A p.Ala114Thr Ala97Thr Mumm et al. 2001 infantile p.Ala114Thr/p.Asp294Ala         ++
5 c.341C>G p.Ala114Gly Ala97Gly Draguet et al. 2004 perinatal

p.Ala114Gly+c.348_349insACCGTC
/p.Gly326Arg

        ++
5 c.341C>T p.Ala114Val Ala97Val Versailles lab march 2016 adult

p.Ala114Val/N

        ++
5 c.346G>T p.Ala116Ser Ala99Ser Versailles lab Jul 2007 adult p.Ala116Ser/p.Asn417Ser         ++
5 c.346G>A p.Ala116Thr Ala99Thr Hu et al. 2000 adult p.Ala116Thr/N 0.8 Lia-Baldini et al. 2001 40.0 Lia-Baldini et al. 2001 ++
5 c.348_349insACCGTC p.Ala116_Tyr117insThrVal Ala99_Tyr100insThrVal Draguet et al. 2004 perinatal p.Ala116Gly+c.348_349insACCGTC
/p.Gly326Arg
        na
5 c.343_348dupACCGCC p.Thr115_Ala116dup Thr98_Ala99dup Versailles lab March 2009 odonto c.348_349insACCGCC         na
5 c.350A>G p.Tyr117Cys Tyr100Cys Whyte et al. 2009 childhood p.Tyr117Cys/p.Thr134His         +
5 c.352C>A p.Leu118Met Leu101Met Riancho-Zarrabeitia et al. 2016 asymtomatic* or very mild symptoms p.Leu118Met/p.Leu118Met         ++
5 c.358G>A p.Gly120Arg Gly103Arg Mornet et al. 1998 perinatal p.Gly120Arg/c.648+1G>A         ++
5 c.361G>A p.Val121Met Val104Met Versailles lab dec. 2015 childhood p.Val121Met/N         ++
5 c.368C>A p.Ala123Asp Ala106Asp Spentchian et al. 2006 perinatal p.Ala123Asp/p.Ser266_His267del         +
5 c.382G>A p.Val128Met Val111Met Mumm et al. 2002 perinatal p.Val128Met/p.Arg223Trp         +
5 c.383_384insG p.Val130GlyfsX6 Val113GlyfsX6 Riancho-Zarrabeitia et al. 2016 asymtomatic* or very mild symptoms c.383_384insG/?         na
5 c.385G>A p.Gly129Arg Gly112Arg Mornet et al. 1998 perinatal p.Gly129Arg/p.Gly491Arg         ++
5 c.388_391delGTAA p.Val130AlafsX34 Val113AlafsX34 Spentchian et al. 2003 perinatal p.Glu311Lys/c.388_391delGTAA         na
5 c.389delT p.Val130GlufsX35 Val113GlufsX35 Spentchian et al. 2003 perinatal c.389delT/c.389delT         na
5 c.392delG p.Ser131ThrfsX34 Ser114ThrfsX34 Mumm et al. 2002 perinat/infant c.392delG/p.Ala348Thr         na
5 c.394G>A p.Ala132Thr Ala115Thr Versailles lab Jul 2006 adult p.Ala132Thr/p.Glu191Lys         ++
5 c.395C>T p.Ala132Val Ala115Val Watanabe et al. 2001 adult p.Ala132Val/? 16.9 Watanabe et al. 2005     ++
5 c.400_401AC>CA p.Thr134His Thr117His Mumm et al. 2002 perinatal p.Thr134His/p.Phe327del         +
5 c.401C>A p.Thr134Asn Thr117Asn Taillandier et al. 2000 perinatal p.Thr134Asn/p.Thr134Asn 20.5 Taillandier et al. 2000     +
5 c.406C>T p.Arg136Cys Arg119Cys Versailles lab oct. 2003 odonto p.Arg136Cys/p.Arg136H         ++
5 c.407G>A p.Arg136His Arg119His Taillandier et al. 1999 infantile p.Arg136His/p.Gly162Val 33.4 Zurutuza et al. 1999 70.0 Fauvert et al. 2009 ++
5 c.407G>T p.Arg136Leu Arg119Leu Yang et al. 2013 childhood p.Arg136Leu/p.Thr389Asn 35 Yang et al. 2013

62

Yang et al. 2013 ++
5 c.422C>A p.Thr141Asn Thr124Asn Whyte et al. 2015 childhood p.Thr141Asn/p.His210Arg         ++
5 c.422C>T p.Thr141Ile Thr124Ile Versailles lab Jul 2008 infantile p.Thr141Ile/p.Pro307Leu         ++
5 c.427delC p.Gln143ArgfsX22 Gln126ArgfsX22 Whyte et al. 2015 childhood c.427delC/p.His482Asn         na
5 c.436G>A p.Glu146Lys Glu129Lys Nielson et al. 2012 asymptomatic*, low BMD p.Glu146Lys/?         ++
5 c.442A>G p.Thr148Ala Thr131Ala Michigami et al. 2005 perinatal p.Thr148Ala/?         ++
5 c.443C>T p.Thr148Ile Thr131Ile Spentchian et al. 2003 infantile p.Thr148Ile/p.Gly162Ser         ++
5 c.454C>T p.Arg152Cys Arg135Cys Versailles lab Nov. 2009 adult p.Arg152Cys/p.Arg184Trp         +
5 c.457T>C p.Trp153Arg Trp136Arg Wenkert et al. 2011 prenatal benign p.Ile412Val/p.Trp153Arg         ++
IVS5 c.472+1G>A     Liu et al. 2010 odonto c.472+1G>A/p.Val374Met         na
IVS5 c.473-2A>G     Riancho-Zarrabeitia et al. 2016 asymtomatic* or very mild symptoms c.473-2A>G/?         na
6 c.480delT     Versailles lab. Jan. 2008 perinatal c.480delT/p.Arg223Trp         na
6 c.484G>A p.Gly162Ser Gly145Ser Spentchian et al. 2003 infantile p.Thr148Ile/p.Gly162Ser         ++
6 c.485G>T p.Gly162Val Gly145Val Taillandier et al. 1999 infantile p.Arg136His/p.Gly162Val 1.3 Zurutuza et al. 1999     ++
6 c.491T>G p.Val164Gly Val147Gly Versailles lab March 2009 infantile p.Val164Gly/p.Asp294Ala         ++
6 c.497C>T p.Thr166Ile Thr149Ile Riancho-Zarrabeitia et al. 2016 asymtomatic* or very mild symptoms p.Thr166Ile/N         ++
6 c.500C>T p.Thr167Met Thr150Met Versailles lab Oct. 2003 infantile p.Thr167Met/p.Glu191Lys 0       +
6 c.508A>G p.Asn170Asp Asn153Asp Mornet et al. 1998 perinatal p.Asn170Asp/p.Asn170Asp 0 Ito et al. 2002     +
6 c.511C>T p.His171Tyr His154Tyr Taillandier et al. 1999 infantile p.His171Tyr/p.Glu191Lys 2.1 Zurutuza et al. 1999     ++
6 c.512A>G p.His171Arg His154Arg Mornet E, unpublished adult p.His171Arg/p.Glu191Lys         ++
6 c.526G>A p.Ala176Thr Ala159Thr Taillandier et al. 2000 childhood p.Ala176Thr/p.Arg246Ser 45.4 Taillandier et al. 2000 58.0 Fauvert et al. 2009 ++
6 c.529G>A p.Ala177Thr Ala160Thr Goseki-Sone et al. 1998 adult p.Ala177Thr/p.Phe327Leu 83.8 Orimo et al. 2001     +
6 c.535G>A p.Ala179Thr Ala156Thr Weiss et al. 1988 perinatal p.Ala179Thr/p.Ala179Thr 18 Shibata et al.1998     ++
6 c.538C>A p.His180Asn His163Asn Versailles lab march 2016 adult p.His180Asn/?         ++
6 c.542C>T p.Ser181Leu Ser164Leu Lia-Baldini et al. 2001 infantile p.Ser181Leu/del(ex12) 1.3 Lia-Baldini et al. 2001 40.3 Lia-Baldini et al. 2001 ++
6 c.544delG p.Ala182LeufsX16 Ala165LeufsX16 Taillandier et al. 1999 perinatal p.Gly249Val/c.544delG         na
6 c.547G>C p.Asp183His Asp166His Versailles lab Nov 2008 infantile p.Asp183H/p.Asp294Ala         +
6 c.550C>T p.Arg184Trp Arg167Trp Mornet et al. 1998 perinatal p.Arg184Trp/p.Trp270Ter 0.6 Lia-Baldini et al. 2001 36.7 Lia-Baldini et al. 2001 ++
6 c.551G>A p.Arg184Gln Arg167Gln Versailles lab. Nov. 2013 Infantile p.Arg184Gln/p.Thr68M         ++
6 c.567C>A p.Asp189Glu Asp172Glu Spentchian et al. 2003 perinatal p.Asp189Glu/p.Asp189Glu         ++
6 c.568_570delAAC p.Asn190del Asn173del Michigami et al. 2005 perinatal c.1559delT/p.Asn190del         na
6 c.571G>A p.Glu191Lys Glu174Lys Henthorn et al. 1992 infantile p.Glu191Lys/p.Asp378Val 88.0 Zurutuza et al. 1999 79.5 Fauvert et al. 2009 ++
6 c.572A>G p.Glu191Gly Glu174Gly Goseki-Sone et al. 1998 odonto p.Glu191Gly/c.1559delT         ++
6 c.575T>C p.Met192Thr Met175Thr Versailles lab Jul 2007 infantile p.Met192Thr/p.Glu311Lys         ++
6 c.577C>G p.Pro193Ala Pro176Ala Mumm et al. 2002 adult p.Ala114Thr/p.Pro193Ala         +
6 c.599G>A p.Gly200Asp Gly183Asp Taillandier et al. 2015 adult p.Gly200Asp/,         ++
6 c.602G>A p.Cys201Tyr Cys184Tyr Taillandier et al. 1999 perinatal c.-195C>T/p.Cys201Tyr 0 Satou et al. 2012     ++
6 c.609C>G p.Asp203Glu Asp186Glu Versailles lab oct. 2004 perinatal p.Asp203Glu/p.Asp203Glu         ++
6 c.614C>T p.Ala205Val Ala188Val Versailles lab aug. 2013 asymptomatic* p.Ala205Val/?         +
6 c.620A>C p.Gln207Pro Gln190Pro Henthorn et al. 1992 perinatal p.Arg71Pro/p.Gln207Pro         ++
6 c.622C>T p.Leu208Phe Leu191Phe Versailles lab april 2009 perinatal p.Leu208Phe/p.Leu208Phe         ++
6 c.629A>G p.His210Arg His193Phe Whyte et al. 2015 childhood p.His210Arg/p.Thr141Asn         +
6 c.630_637dupTAACATCA p.Arg213IlefsX8 Arg196IlefsX8 Versailles lab June 2011 perinatal c.630_637dupTAACATCA/c.792G>A         na
6 c.631A>G p.Asn211Asp Asn194Asp Taillandier et al. 2001 infantile p.Ala116Thr/p.Asn211Asp         ++
6 c.634A>T p.Ile212Phe Ile195Phe Souka et al. 2002 perinatal p.Ile212Phe/p.Glu354Asp         +
6 c.644T>C p.Ile215Thr Ile198Phe Versailles lab. march 2011 infantile p.Ile215Thr/p.Ser181Leu         ++
IVS6 c.648+1G>T     Brun-Heath et al. 2005 perinatal c.648+1G>T/p.Asp294Ala         na
IVS6 c.648+1G>A     Mornet et al. 1998 perinatal p.Gly120Arg/c.648+1G>A         na
IVS6 c.648+2_3insT     Versailles lab jan 2013 perinatal c.648+2_3insT/p.Ala399Val         na
IVS6 c.649-1_3delinsAA     Versailles lab Jul 2006 perinatal c.649-1_3delinsAA/c.649-1_3delinsAA         na
7 c.650delTinsCTAA p.217delValinsAlaLys 200delValinsAlaLys Chang et al. 2011 perinatal c.650delTinsCTAA/p.Phe327del         na
7 c.653T>C p.Ile218Thr Ile201Thr

Utsch et al., 2009

perinatal p.Ile218Thr/p.Arg391Cys 3.7 Utsch et al., 2009     ++
7 c.655A>G p.Met219Val Met202Val Yang et al. 2013 odonto p.Met219Val/p.Ala111Thr 75 Yang et al. 2013

80

Yang et al. 2013 +
7 c.658G>A p.Gly220Arg Gly203Arg Versailles lab Dec 2011 perinatal p.Gly220Arg/p.Gly220Arg         ++
7 c.659G>T p.Gly220Val Gly203Val Taillandier et al. 2001 odonto p.Glu191Lys/p.Gly220Val         ++
7 c.659G>C p.Gly220Ala Gly203Ala Spentchian et al. 2003 perinatal p.Gly220Ala/p.Gly220A         ++
7 c.661G>C p.Gly221Arg Gly204Arg Versailles lab March 2009 perinatal p.Gly221Arg/?         ++
7 c.662_663insG p.Gly222TrpfsX10 Gly205TrpfsX10 Mornet E, unpublished perinatal p.Gln44Ter/c.662_663insG         na
7 c.662delG p.Gly221ValfsX56 Gly204ValfsX56 Spentchian et al. 2003 perinatal p.Arg272Leu/c.662delG         na
7 c.662G>T p.Gly221Val Gly204Val Versailles lab oct. 2004 perinatal p.Gly221Val/p.Met355T         ++
7 c.667C>T p.Arg223Trp Arg206Trp Mornet et al. 1998 perinatal p.Arg223Trp/? 2.8 Lia-Baldini et al. 2001 51.9 Lia-Baldini et al. 2001 ++
7 c.668G>A p.Arg223Gln Arg206Gln Mumm et al. 2002 perinatal p.Arg223Gln/deletion 2.9 Zhu et al. 2012     ++
7 c.670A>G p.Lys224Glu Lys207Glu Mochizuki et al. 2000 infantile p.Lys224Glu/p.Gly426Cys 43 Michigami et al. 2005     ++
7 c.677T>C p.Met226Thr Met209Thr Baumgartner-Sigl et al. 2007 infantile p.Met226Thr/p.Thr371Ile         ++
7 c.704A>G p.Glu235Gly Glu218Gly Taillandier et al. 2001 adult p.Glu235Gly/p.Ala399Ser 3.6 Mornet et al. 2001     ++
7 c.715G>T p.Asp239Tyr Asp222Tyr Saraff et al. 2016 asymptomatic* p.Asp239Tyr/p.Asp239Tyr         +
7 c.734C>T p.Thr245Met Thr228Met Versailles lab May 2016 Prenatal benign p.Thr245Met/?         ++
7 c.738G>T p.Arg246Ser Arg229Ser Taillandier et al. 2000 childhood p.Ala176Thr/p.Arg246Ser 4.4 Taillandier et al. 2000     ++
7 c.746G>T p.Gly249Val Gly232Val Fedde et al. 1996 perinatal p.Gly249Val/N 34.5 Lia-Baldini et al. 2001 70.5 Lia-Baldini et al. 2001 +
7 c.791A>G p.Lys264Arg Lys247Arg Brun-Heath et al. 2007 perinatal p.Lys264Arg/p.Asp378Val         +
7 c.792G>A p.Lys264Lys Lys247Lys Versailles lab june 2011 perinatal p.Lys264Lys/c.630_637dupTAACATCA         na (splice)
8 c.797_802del p.Ser266_His267del Ser249_His250del Spentchian et al. 2006 perinatal p.Ala123Asp/p.Ser266_p.His267del         na
8 c.809G>A p.Trp270Ter Trp253Ter Mornet et al. 1998 perinatal p.Arg184Trp/p.Trp270Ter 1.2 Zurutuza et al. 1999     na
8 c.814C>T p.Arg272Cys Arg255Cys Spentchian et al. 2006 perinatal p.Arg272Cys/p.Thr134His         ++
8 c.814delC p.Arg272AlafsX5 Arg255AlafsX5 Versailles lab June 2011 perinatal c.814delT/p.His381Arg         na
8 c.815G>T p.Arg272Leu Arg255Leu Spentchian et al. 2003 perinatal p.Arg272Leu/c.662delG         ++
8 c.815G>A p.Arg272His Arg255His Brun-Heath et al. 2005 infantile p.Arg272His/p.Arg272His 6.8 Brun-Heath et al. 2005     ++
8 c.818C>T p.Thr273Met Thr256Met Nielson et al. 2012 asymptomatic*, low BMD p.Thr273Met/?         +
8 c.824T>C p.Leu275Pro Leu258Pro Orimo et al. 2002 childhood p.Leu275Pro/p.Ala177Ter 3.3 Orimo et al. 2001     ++
8 c.853_854insGATC p.Tyr285Ter Tyr268Ter Michigami et al. 2005 perinatal c1559delT/p.Tyr285Ter         na
IVS8 c.862+5G>A     Taillandier et al. 1999 infantile c.862+5G>A/c.862+5G>A         na
9 c.865C>T p.Leu289Phe Leu272Phe Sugimoto et al. 1998 infantile p.Leu289Phe/? 50 Sugimoto et al. 1998     ++
9 c.871G>A p.Glu291Lys Glu274Lys Mornet et al. 1998 infantile p.Glu191Lys/p.Glu291Lys 8.3 Zurutuza et al. 1999     ++
9 c.871G>T p.Glu291Ter Glu274Ter Taillandier et al. 2000 perinatal p.Ala111Thr/p.Glu291Ter         na
9 c.871G>C p.Glu291Gln Glu274Gln Versailles lab Jun 2010 perinatal p.Glu291Gln/p.Glu291Gln         ++
9 c.874C>A p.Pro292Ter Pro275Ter Brun-Heath et al. 2005 infantile p.Pro292Thr/p.Ala33Val 4.0 Brun-Heath et al. 2005     ++
9 c.875_881delCAGGGGAinsT     Belachew et al. 2013 perinatal c.875_881delCAGGGGAinsT/c.1559delT         na
9 c.876_881delAGGGGA p.Gly293_Asp294del Gly276_Asp277del Spentchian et al. 2003 perinatal p.Gly293_p.Asp294del/c.962delG         na
9 c.880G>T p.Asp294Tyr Asp277Tyr Taillandier et al. 2001 infantile p.Ala176Thr/p.Asp294Tyr         ++
9 c.881A>C p.Asp294Ala Asp277Ala Henthorn et al. 1992 infantile p.Arg71Cys/p.Asp294Ala 35 Fukushi-Irié et al. 2000     ++
9 c.883A>G p.Met295Val Met278Val Mornet et al. 2001 childhood p.Glu191Lys/p.Met295Val         +
9 c.884T>C p.Met295Thr Met278Thr Brun-Heath et al. 2005 perinatal p.Met295Ter/p.Arg223Trp 8.5 Brun-Heath et al. 2005     +
9 c.885G>A p.Met295Ile Met278Ile Michigami et al. 2005 perinatal p.Met295Ile/c.1559delT         +
9 c.886C>T p.Gln296Ter Gln279Ter Plendl et al. 2011 adult p.Gln296Ter/?         na
9 c.889T>G p.Tyr297Asp Tyr280Asp Brun-Heath et al. 2005 childhood p.Arg136His/p.Tyr297Asp 1.3 Brun-Heath et al. 2005     ++
9 c.889T>C p.Tyr297His Tyr280His Bertola et al. 2009 perinatal p.Tyr297His/c.648+1G>A         ++
9 c.889T>A p.Tyr297Asn Tyr280Asn Research center for medical genetics, Moscow, Oct. 2015 Childhood p.Tyr297Asn/?         ++
9 c.891C>A p.Tyr297Ter Tyr280Ter Balasubramaniam et al. 2010 Infantile p.Tyr297Ter/p.Gly491Arg         na
9 c.892G>A p.Glu298Lys Glu281Lys Orimo et al. 1994 infantile p.Glu298Lys/c.1559delT         ++
9 c.896T>C p.Leu299Pro Leu282Pro Versailles lab oct. 2003 infantile p.Leu299Pro/p.Leu299Pro 9.7 Michigami et al. 2005     ++
9 c.917A>T p.Asp306Val Asp289Val Taillandier et al. 1999 infantile p.Asp306Val/p.Asp306Val 0 Ishida et al. 2003     ++
9 c.919C>T p.Pro307Ser Pro290Val Versailles lab oct. 2004 infantile p.Pro307Ser/p.Met467Thr         ++
9 c.920C>T p.Pro307Leu Pro290Leu Versailles lab Jul. 2006 childhood p.Pro307Leu/p.Ser181Leu         ++
9 c.928_929delTC p.Ser310ArgfsX27 Ser293ArgfsX27 Brun-Heath et al. 2005 perinatal p.Thr394Ala/c.928_929delTC         na
9 c.931G>A p.Glu311Lys Glu294Lys Spentchian et al. 2003 perinatal p.Glu311Lys/c.388_391delGTAA         ++
9 c.952C>T p.Gln318Ter Gln301Ter Versailles lab Dec 2011 perinatal p.Gln318Ter/p.Asp406Asn         na
9 c.963delG p.Lys322ArgfsX44 Lys305ArgfsX44 Spentchian et al. 2003 perinatal p.Gly293_Asp294del/c.963delG         na
9 c.969C>G p.Asn323Lys Asn306Lys Versailles lab oct. 2009 childhood p.Asn323Lys/c.648+1G>A         ++
9 c.976G>C p.Gly326Arg Gly309Arg Litmanovitz et al. 2002 perinatal p.Gly326Arg/p.Glu291Lys         ++
9 c.977G>T p.Gly326Val Gly309Val Versailles lab Jul 2008 perinatal p.Gly326Val/p.Gly326Val         ++
9 c.979T>G p.Phe327Cys Phe310Cys Mornet et al. 2001 perinatal p.Thr134Asn/p.Phe327Cys         ++
9 c.979_980TT>GG p.Phe327Gly Phe310Gly Taillandier et al. 2001 adult p.Glu191Lys/p.Phe327Gly         ++
9 c.979T>C p.Phe327Leu Phe310Leu Ozono et al. 1996 infantile p.Phe327Leu/p.Gly456Arg 72 Cai et al. 1998     ++
9 c.982T>C p.Phe328Leu Phe311Leu Michigami et al. 2005 perinatal non-lethal p.Phe328Leu/p.Thr100Met 10 Michigami et al. 2005     ++
9 c.984_986delCTT p.Phe328del Phe311del Orimo et al. 1997 infantile p.Phe328del/c.1559delT 10 Michigami et al. 2005     na
IVS9 c.997+1G>T     Liu et al. 2010 odonto c.997+1G>T/p.Tyr388His         na
IVS9 c.997+2T>A     Taillandier et al. 2000 perinatal c.997+2T>A/p.Cys489Ser         na
IVS9 c.997+2T>G     Brun-Heath et al. 2005 perinatal c.997+2T>G/c.997+2T>G         na
IVS9 c.997+3A>C     Mornet et al. 1998 perinatal c.997+3A>C/c.997+3A>C         na
IVS9 c.997+3A>G     Wenkert et al. 2011 prenatal benign c.1181_1182delCT/c.997+3A>G         na
IVS9 c.998-1G>T     Taillandier et al. 2001 perinatal p.Glu191Lys/c.998-1G>T         na
10 c.1000G>C p.Gly334Arg Gly317Arg Fauvert et al. 2009 odonto p.Gly334Arg/N 5.0 Fauvert et al. 2009 39.0 Fauvert et al. 2009 ++
10 c.1001G>A p.Gly334Asp Gly317Asp Greenberg et al. 1993 perinatal p.Gly334Asp/p.Gly334Asp 0 Fukushi et al. 1998 40.0 Fauvert et al. 2009 ++
10 c.1010A>G p.Asp337Gly Asp320Gly Whyte et al. 2015 childhood p.Asp337Gly/p.Glu191Lys         ++
10 c.1015G>A p.Gly339Arg Gly322Arg Mumm et al. 2002 perinatal p.Gly339Arg/p.Ala176Thr 1.1 Fauvert et al. 2009 33.0 Fauvert et al. 2009 ++
10 c.1015G>C p.Gly339Arg Gly322Arg Versailles lab. Jan 2010 adult p.Gly339Arg/p.Glu191Lys         ++
10 c.1016G>A p.Gly339Glu Gly322Glu Versailles lab oct. 2004 infantile p.Gly339Glu/p.Val128Met         ++
10 c.1042G>A p.Ala348Thr Ala331Thr Taillandier et al. 2000 infantile p.Glu191Lys/p.Ala348Thr 33.2 Taillandier et al. 2000     ++
10 c.1044_1055del12 p.Leu349_Ala352del Leu332_Ala335del Spentchian et al. 2006 perinatal p.Leu349_p.Ala352del/p.Gly491Arg         na
10 c.1062G>C p.Glu354Asp Glu337Asp Souka et al. 2002 perinatal p.Ile212Phe/p.Glu354Asp         ++
10 c.1064T>C p.Met355Thr Met338Thr Versailles lab oct. 2004 perinatal p.Gly221Val/p.Met355Thr         ++
10 c.1065G>A p.Met355Ile Met338Ile Versailles lab. Jan. 2008 infantile p.Met355Ile/p.Arg391Cys         ++
10 c.1068C>A p.Asp356Glu Asp339Glu Versailles lab Apr 2011 perinatal p.Asp356Glu/p.Arg223Gln         ++
10 c.1070G>T p.Arg357Leu Arg340Leu Nielson et al. 2012 asymptomatic*, low BMD p.Arg357Leu/?         +
10 c.1072G>A p.Ala358Thr Ala 341Thr Research center for medical genetics, Moscow, Nov. 2015 adult p.Ala358Thr/?         ++
10 c.1077C>G p.Ile359Met Ile342Met Whyte et al. 2012 infantile p.Asp359Met/p.Asp378Val         ++
10 c.1083_1084dup p.Ser364ArgfsX42 Ser347ArgfsX42 Riancho-Zarrabeitia et al. 2016 asymtomatic* or very mild symptoms c.1083_1084dup/?         na
10 c.1097C>A p.Thr366Asn Thr349Asn Versailles lab march 2016 asymtomatic* or very mild symptoms p.Thr366Asn/?         ++
10 c.1101_1103delCTC p.Ser368del Ser351del Versailles lab oct. 2004 perinatal c.1101_1103delCTC/p.Thr389Ile         na
10 c.1112C>T p.Thr371Ile Thr354Ile Baumgartner-Sigl et al. 2007 infantile p.Met226Thr/p.Thr371Ile         ++
10 c.1120G>A p.Val374Met Val357Met Versailles lab oct. 2004 adult p.Val374Met/p.Glu298Lys 57.6 Zhu et al. 2012     +
10 c.1130C>T p.Ala377Val Ala360Val Mornet et al. 2001 perinatal p.Ala377Val/p.Ala377Val         ++
10 c.1132G>T p.Asp378Tyr Asp361Tyr Versailles lab. Apr. 2010 odonto. p.Asp378Tyr/N         ++
10 c.1132G>C p.Asp378His Asp361His Whyte et al. 2015 childhood p.Asp378H/p.Glu191Lys         ++
10 c.1133A>T p.Asp378Val Asp361Val Henthorn et al. 1992 infantile p.Glu191Lys/p.Asp378Val 1.2 Lia-Baldini et al. 2001 19.9 Lia-Baldini et al. 2001 ++
10 c.1142A>G p.His381Arg His364Arg Taillandier et al. 2000 infantile p.Ala40Val/p.His381Arg         ++
10 c.1144G>A p.Val382Ile Val365Ile Goseki-Sone et al. 1998 childhood p.Phe327Leu/p.Val382Ile 0 Watanabe et al. 2002 30.0 Takinami et al. 2004 ++
10 c.1162T>C p.Tyr388His Tyr371His Liu et al. 2010 odonto p.Tyr388His/c.997+1G>T 39.7 Zhu et al. 2012 60 Yang et al. 2013 ++
10 c.1166C>T p.Thr389Ile Thr372Ile Versailles lab oct. 2004 perinatal p.Thr389Ile/p.Ser368del         ++
10 c.1166C>A p.Thr389Asn Thr372Asn Yang et al. 2013 childhood p.Thr389Asn/p.Arg136Leu 0 Yang et al. 2013

40

Yang et al. 2013 ++
10 c.1171C>T p.Arg391Cys Arg374Cys Zurutuza et al. 1999 childhood p.Glu191Lys/p.Arg391Cys 10.3 Zurutuza et al. 1999 50.5 Fauvert et al. 2009 ++
10 c.1172G>A p.Arg391His Arg374His Orimo et al. 2002 childhood p.Arg391His/? 3.7 Orimo et al. 2001 29.1 Fauvert et al. 2009 ++
10 c.1171delC p.Arg391ValfsX12 Arg374ValfsX12 Taillandier et al. 1999 infantile p.Met62Leu/c.1171delC         na
10 c.1175G>C p.Gly392Ala Gly375Ala Versailles lab. Jan. 2008 perinatal p.Gly392Ala/p.Arg136Cys         ++
10 c.1178A>T p.Asn393Ile Asn376Ile Versailles lab March 2013 infantile moderate p.Asn393Ile/p.Glu191Lys         +
10 c.1181_1182delCT p.Ser394fs Ser377fs Wenkert et al. 2011 prenatal benign c.1181_1182delCT/c.997+3A>G         na
10 c.1183A>G p.Ile395Val Ile378Val Wenkert et al. 2011 prenatal benign p.Ile395Val/p.Trp153Arg         ++
10 c.1184T>C p.Ile395Thr Ile378Thr Versailles lab Jul. 2006 perinatal p.Ile395Thr/p.Glu191Lys         ++
IVS10 c.1189+5delG     Whyte et al. 2015 childhood c.1189+5delG/p.Ala443Val         na
11 c.1190G>A p.Gly397Asp Gly380Asp Whyte et al. 2015 odonto. p.Gly397Asp/N         ++
11 c.1195G>T p.Ala399Ser Ala382Ser Taillandier et al. 2001 adult p.Glu235Gly/p.Ala399Ser         ++
11 c.1196C>T p.Ala399Val Ala382Val Spentchian et al. 2006 adult p.Ala399Val/p.Ala33Val         ++
11 c.1199C>T p.Pro400Leu Pro383Leu Spentchian et al. 2006 infantile p.Pro400Leu/p.Pro400Leu         ++
11 c.1214_1215delCA p.Thr405ArgfsX22 Thr388ArgfsX22 Versailles lab Jul. 2006 adult c.1214_1215delCA/p.Glu191Lys         na
11 c.1216_1219delGACA p.Asp406ArgfsX77 Asp389ArgfsX77 Brun-Heath et al. 2005 perinatal c.1216_1219delGACA/?         na
11 c.1216G>A p.Asp406Asn Asp389Asn Versailles lab Dec 2011 perinatal p.Gln318Ter/p.Asp406Asn         -
11 c.1217A>G p.Asp406Gly Asp389Gly Taillandier et al. 2000 odonto. p.Asp406Gly/p.Arg450His 14.9 Taillandier et al. 2000     -
11 c.1228T>C p.Phe410Leu Phe393Leu Versailles lab oct. 2004 infantile p.Phe410Leu/p.Glu191Lys         +
11 c.1231A>G p.Thr411Ala Thr394Ala Brun-Heath et al. 2005 perinatal p.Thr411Ala/c.926_927delTC 0.3 Brun-Heath et al. 2005     ++
11 c.1240C>A p.Leu414Met Leu397Met Mumm et al. 2002 perinatal p.Leu414Met/p.Asp294Ala 0.4 Fauvert et al. 2009 23.5 Fauvert et al. 2009 ++
11 c.1250A>G p.Asn417Ser Asn400Ser Sergi et al. 2001 perinatal p.Asn417Ser/c.648+1G>A 3 Fauvert et al. 2009 26.5 Fauvert et al. 2009 ++
11 c.1256delC p.Pro419LeufsX65 Pro402LeufsX65 Taillandier et al. 2000 perinatal c.1256delC/?         na
11 c.1258G>A p.Gly420Ser Gly403Ser Glaser et al. 2004 perinatal p.Gly420Ser/p.Gly420Ser

0

Makita et al. 2012

40

Makita et al. 2012 ++
11 c.1259G>C p.Gly420Ala Gly403Ala Fauvert et al. 2009 childhood p.Gly420Ala/p.Glu191Lys 4.2 Fauvert et al. 2009 19.7 Fauvert et al. 2009 ++
11 c.1268T>C p.Val423Ala Val406Ala Taillandier et al. 2001 perinatal p.Ala116Thr/p.Val423Ala 15.7 Numa et al. 2008     +
11 c.1270G>A p.Val424Met Val407Met Versailles lab jan. 2007 adult p.Val424Met/p.Val424Met         +
11 c.1271T>C p.Val424Ala Val407Ala Zhang et al. 2012 adult p.Val424Ala/p.Val424Ala         +
11 c.1276G>T p.Gly426Cys Gly409Cys Mochizuki et al. 2000 infantile p.Leuys224Ala/p.Gly426Cys 18.5 Michigami et al. 2005     ++
11 c.1276G>A p.Gly426Ser Gly409Ser Versailles lab Apr 2011 infantile p.Gly426Ser/p.Gly426Ser         ++
11 c.1277G>A p.Gly426Asp Gly409Asp Mumm et al. 2002 childhood p.Gly426Asp/p.Glu191Lys         ++
11 c.1282C>T p.Arg428Ter Arg411Ter Taillandier et al. 1999 perinatal p.Arg428Ter/p.Arg428Ter         na
11 c.1283G>C p.Arg428Pro Arg411Pro Spentchian et al. 2006 perinatal p.Arg428Pro/c.997+2T>A         ++
11 c.1283G>A p.Arg428Gln Arg411Gln Versailles lab Jul. 2010 prenatal benign p.Arg428Gln/N         ++
11 c.1283G>T p.Arg428Leu Arg411Leu Plendl et al. 2011 adult p.Arg428Leu/?         ++
11 c.1285G>A p.Glu429Lys Glu412Lys Versailles lab Jul. 2006 odonto. p.Glu429Lys/? 1.3 Fauvert et al. 2009 31.0 Fauvert et al. 2009 ++
11 c.1289A>G p.Asn430Ser Asn413Ser Whyte et al. 2015 infantile p.Asn430Ser/p.Glu191Lys 0 Komaru et al. 2016

58

Komaru et al. 2016 ++
11 c.1292T>C p.Val431Ala Val414Ala Taillandier et al. 2015 odonto. p.Val431Ala/N         +
11 c.1306T>C p.Tyr436His Tyr419His Henthorn et al. 1992 childhood p.Ala33Val/p.Tyr436His         ++
11 c.1307A>G p.Tyr436Cys Tyr419Cys Taketani et al. 2013 Infantile p.Tyr436Cys/c.1559delT         ++
11 c.1307A>C p.Tyr436Ser Tyr419Ser Nielson et al. 2012 asymptomatic*, low BMD p.Tyr436Ser/N         ++
12 c.1313A>T p.His438Leu His421Leu Versailles lab oct. 2009 infantile p.His438Leu/p.His438Leu         ++
12 c.1318_1320 delAAC p.Asn440del Asn423del Martins et al. 2013 odonto. p.Arg152Cys/p.Asn440del         na
12 c.1323C>A p.Tyr441Ter Tyr424Ter Hofmann et al. 2013 perinatal p.Y441Ter/p.Arg223Trp 1.0 Hofmann et al. 2013 58.3 Hofmann et al. 2013 na
12 c.1328C>T p.Ala443Val Ala426Val Fauvert et al. 2009 adult p.Ala443Val/N 1.4 Fauvert et al. 2009 53.1 Fauvert et al. 2009 ++
12 c.1333T>C p.Ser445Pro Ser428Pro Mornet et al. 1998 infantile p.Ser445Pro/? 2.1 Zurutuza et al. 1999 35.1 Fauvert et al. 2009 +
12 c.1336G>A p.Ala446Thr Ala429Thr Versailles lab Jan 2013 perinatal p.Ala446Thr/p.Ala446Thr         ++
12 c.1349G>A p.Arg450His Arg433His Taillandier et al. 2000 odonto. p.Asp406Gly/p.Arg450His         +
12 c.1348C>T p.Arg450Cys Arg433Cys Mornet et al. 1998 infantile p.Arg450Cys/p.Arg450Cys 4.0 Zurutuza et al. 1999     +
12 c.1354G>A p.Glu452Lys Glu435Lys Spentchian et al. 2003 perinatal p.Ala111Thr/p.Glu452Lys 1.4 Fauvert et al. 2009 27.5 Fauvert et al. 2009 ++
12 c.1361A>G p.His454Arg His437Arg Versailles lab oct. 2003 childhood p.Glu191Lys/p.His454Arg         ++
12 c.1363G>A p.Gly455Ser Gly438Ser Draguet et al. 2004 adult p.Gly455Ser/p.Gly491Arg 71.0 Brun-Heath et al. 2007     ++
12 c.1364G>A p.Gly455Asp Gly438Asp Versailles lab jan. 2007 perinatal p.Gly455Asp/p.Gly455Asp         ++
12 c.1366G>T p.Gly456Trp Gly439Trp Versailles lab oct. 2003 childhood p.Gly456Trp/? 0.8 Fauvert et al. 2009 14.5 Fauvert et al. 2009 ++
12 c.1366G>A p.Gly456Arg Gly439Arg Ozono et al. 1996 infantile p.Gly456Arg/? 1.5 Fauvert et al. 2009 50.5 Fauvert et al. 2009 ++
12 c.1372G>A p.Asp458Asn Asp441Asn Versailles lab Dec 2011 adult p.Asp458Asn/p.Glu191Lys         ++
12 c.1373A>G p.Asp458Gly Asp441Gly Plendl et al. 2011 infantile p.Asp458Gly/p.Glu191Lys         ++
12 c.1375G>A p.Val459Met Val442Met Taillandier et al. 2000 infantile p.Ala51Val/p.Val459Met         ++
12 c.1375G>T p.Val459Leu Val442Leu Versailles lab oct. 2004 perinatal p.Val459Leu/p.Glu452Lys 0 Fauvert et al. 2009 41.1 Fauvert et al. 2009 ++
12 c.1381G>A p.Val461Ile Val444Ile Nielson et al. 2012 asymptomatic*, low BMD p.Val461Ile/?         +
12 c.1397C>T p.Pro466Leu Pro449Leu Versailles lab oct. 2003 perinatal p.Pro466Leu/?         +
12 c.1400T>C p.Met467Thr Met450Thr Versailles lab oct. 2004 infantile p.Met467Thr/p.Pro307Ser         +
12 c.1402G>A p.Ala468Thr Ala451Thr Spentchian et al. 2003 perinatal p.Ala468Thr/p.Ala468Thr         ++
12 c.1412_1429del18 p.Leu471_Glu476del Leu454_Glu459del Plendl et al. 2011 adult p.Leu471_Glu476del/?         na
12 c.1414C>T p.His472Tyr His455Tyr V. Buzzi, P. La Verde, Milan, Italy perinatal p.His472Tyr/p.Thr100Met         ++
12 c.1417G>A p.Gly473Ser Gly456Ser Mornet et al. 1998 perinatal p.Ala40Val/p.Gly473Ser         ++
12 c.1426G>A p.Glu476Lys Glu459Lys Taillandier et al. 1999 perinatal p.Ala111Thr/p.Glu476Lys         ++
12 c.1427A>G p.Glu476Gly Glu459Gly Mornet et al. 2001 perinatal p.Glu476Gly/p.Glu476Gly         ++
12 c.1427A>C p.Glu476Ala Glu459Ala Versailles lab March 2009 adult p.Glu476Ala/? 0.4 Fauvert et al. 2009 39.3 Fauvert et al. 2009 ++
12 c.1433A>T p.Asn478Ile Asn461Ile Taillandier et al. 2000 childhood p.Asn478Ile/N 1.1 Lia-Baldini et al. 2001 38.2 Lia-Baldini et al. 2001 ++
12 c.1444C>A p.His482Asn His465Asn Nielson et al. 2012 asymptomatic*, low BMD p.His482Asn/N         ++
12 c.1444_1445insC p.His482Profs His465Profs Brun-Heath et al. 2005 perinatal c.1444_1445insC/p.Gly334Asp         na
12 c.1460C>T p.Ala487Val Ala470Val Taillandier et al. 2015 perinatal p.Ala487Val/p.Phe327del         ++
12 c.1466G>C p.Cys489Ser Cys472Ser Taillandier et al. 2000 perinatal p.Cys489Ser/c.997+2T>A 9.4 Taillandier et al. 2000     ++
12 c.1468A>T p.Ile490Phe Ile473Phe Lia-Baldini et al. 2001 adult p.Ile490Phe/? 37.1 Lia-Baldini et al. 2001 77.4 Lia-Baldini et al. 2001 +
12 c.1471G>A p.Gly491Arg Gly474Arg Mornet et al. 1998 perinatal p.Gly129Arg/p.Gly491Arg         ++
12 c.1474delG p.Ala492ProfsX29 Ala475ProfsX29 Brun-Heath et al. 2005 odonto c.1474delG/p.Arg136His         na
12 c.1553_1569del17 p.Tyr518Phefs Tyr501Phefs Versailles lab nov. 2009 perinatal c.1553_1569del/p.Asp294Ala         na
12 c.1559delT p.Leu520ArgfsX86 Leu503ArgfsX86 Orimo et al. 1994 infantile p.Glu298Lys/c.1559delT 28 Komaru et al. 2005     na


Large deletions

deletion of exon 1     Versailles lab july 2012 perinatal homozygote         na
deletion exon 1 - IVS1 - exon 2     Versailles lab May 2016 infantile heterozygote         na
deletion of exon 2     Versailles lab july 2013 perinatal homozygote         na
deletion of exons 3-5     Spentchian et al. 2006 perinatal homozygote         na
deletion of exon 9 (3' part)     Versailles lab dec. 2015 prenat. benign compound heterozygote with p.Arg136His         na
deletion of exon 12 (3' part)     Spentchian et al. 2006 infantile compound heterozygote
with p.Ser164Leu
        na

* Phenotype "asymptomatic": repeatedly low serum alkaline phosphatase, no hypophosphatasia clinical symptom

 

Statistics

Type of mutation Number of mutations %
Missense 236 74.5
Small deletions 33 10.4
Splicing 19 6.0
Nonsense 11 3.5
Small insertions 9 2.8
Large deletions 6 1.9
Ins/Del 2 0.6
Regulatory 1 0.3
Total 317 100

 

 

 

 

Legend to database items

Nomenclature : see the nomenclature section below.
Reference : reference of the publication reporting the mutation.
Clinical form : clinical form of the patient in whom the mutation was detected for the first time.
Genotype : genotype of the patient in whom the mutation was detected for the first time.
? : uncharacterized allele (only one detected mutation without molecular, pedigree, or in silico evidence of dominant transmission).
N : normal allele (dominant mutation on the other chromosome, evidenced by molecular, pedigree, or in silico data.
%WT : residual activity of the mutant protein. Alkaline phosphatase activity of cells transfected with mutant cDNAs, expressed in percentage of the activity found in cells transfected with wild type (WT) cDNA.
% 50/50 : dominant negative effect of the mutation. Alkaline phosphatase activity of cells co-transfected with equal quantities of wild type and mutant cDNAs, expressed in percentage of the activity found in cells transfected with wild type (WT) cDNA. For mutations producing no residual activity, the value is expected to be 50% if there is no dominant negative effect, and <50% if there is a dominant negative effect (Lia-Baldini et al. 2001).
unp. : unpublished.
Conservation : conservation of the affected amino acid among 58 mammalian TNSALP according to Silvent et al. (2014). ++ conserved residue ; + conservative changes only, - residue not conserved, na not applicable.

Nomenclature

Nucleotides numbering is given according to Weiss et al. 1988, the Nomenclature Working Group (S.E. Antonarakis and the Nomenclature Working Group, Hum. Mut. 11:1-3, 1998) and the HGVS recommendations: the first nucleotide (+1) corresponds to the A of the ATG initiation codon. The reference cDNA sequence is NM_000478.4

Amino acids numbering is given according to both the standardized and the non-standardized nomenclatures.
The standardized nomenclature follows the HGVS recommendations: the first codon is the ATG initiation codon.
The non-standardized nomenclature was used in publications before 2008-2009 : this nomenclature takes into account of a 17-residues signal peptide, i.e. the ATG initiation codon is numbered as residue minus (-)17 (Weiss et al. 1988). The reference cDNA sequence is NM_000478.4

p: protein numbering; c: nucleotide numbering of the coding sequence.

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