ALANINE:GLYOXYLATE AMINOTRANSFERASE (AGXT) GENE

(PRIMARY HYPEROXALURIA TYPE 1)

MUTATION DATA BASE

REFERENCE SEQUENCES: c.DNA: NM_000030 g.DNA: NG_008005.1

Nomenclature: HGVS guidelines (http://www.hgvs.org/rec.html) Table 1: Polymorphic variants and those of unknown significance Table 2: Missense and nonsense mutations Table 3: Splice site mutations Table 4: Deletions and insertions Date: 18 August 2017 (future updates will not be made) Curator: Dr Gill Rumsby Disclaimer: While every effort has been made to confirm the accuracy of this database, the author can take no responsibility for errors which have occurred.

Table 1: Polymorphic variants and those of unknown significance (VUS) in the AGXT gene

Location Sequence variant Codon/effect Major (Pro11) or minor (Leu11)

haplotype†

In vitro activity (% of normal) or how

proven

Frequency in controls

SNP database

Original Reference

Exon 1 c.26C>A p.Thr9Asn major 138% (Williams and Rumsby, 2007) 0.01

(Frishberg et al., 2005; Monico et al., 2005)

Exon 1 c.27C>A‡ p.Thr9Thr major n/a (Williams et al.,2009)

Exon 1 c.32C>T p.Pro11Leu minor

64% (Lumb and Danpure, 2000). Defines the ‘AGXT minor’ allele

0.20 rs34116584 (Purdue et al., 1990)

Exon 1 c.32C>A p.Pro11His major 55% (Williams et al.,2009)

Exon 1 c.35A>G p.Lys12Arg major Sift predicts tolerated

Does not track with disease

Williams and Rumsby, unpublished

Exon 1 c.65A>G§ p.Asn22Ser major 0.05 rs34885252 (Williams et al.,2009)

Intron 1 c.165+16A>G n/a

minor (the A variant occasionally on minor)

n/a (Williams et al.,2009)

Intron 1 c.165+83C>T n/a minor n/a (Williams et al.,2009)

Intron 1 c.165+84C>T n/a minor n/a (Williams et al.,2009)

Intron 1 c.165+19_165+92dup74 n/a minor (occasionally major)

n/a 0.24 (Purdue et al., 1991a)

Intron 1 c.166-96T>A n/a minor n/a (Williams et al.,2009)

Intron 1 c.166-100A>C n/a minor n/a (Williams et al.,2009)

Intron 1 c.166-54C>T n/a minor n/a (Williams et al.,2009)

Intron 1 c.166-47T>C n/a minor n/a (Williams et al.,2009)

Intron 1 c.166-14C>T n/a major n/a (Williams et al.,2009)

Exon 2 c.264C>T p.Ala88Ala minor n/a 0.21 rs35698882 (Danpure et al., 1994a)

Intron 2 c.358+13C>T n/a minor n/a 0.20 rs34995778 (Von Schnakenburg, 1998)

Intron 2 c.358+56_358+64del9 n/a major n/a (Williams et al.,2009)

Intron 3 c.423+29C>T n/a n/a Rumsby et al. 2010

Intron 3 c.423+36A>C n/a major n/a (Williams et al.,2009)

Intron 3 c.423+45T>G n/a n/a Rumsby et al. 2010

Intron 3 c.424-12_13dupC n/a major n/a (Williams et al.,2009)

Intron 3 c.424-16G>A n/a major n/a Rumsby, unpublished

Exon 4 c.489G>A p.Leu163Leu n/a (Williams et al.,2009)

Intron 4 c.524+91C>T n/a n/a 0.29 (Monico et al., 2007)

Intron 4 VNTR (29/32)n n/a minor/major. Minor typically with largest repeat

n/a (Danpure et al., 1994b)

Exon 5 c.590G>A§ p.Arg197Gln major Mutation taster predicts benign.

(Williams et al.,2009) Incorrectly

reported as G>T. Found in cis with c.557C>T in PH2 patient

Exon 6 c.654G>A p.Ser218Ser major n/a 0.06 rs33958047

(Monico et al., 2007; Von Schnakenburg. 1998)

Intron 6 c.680+17C>T n/a minor n/a 0.18 rs11693280 (Monico et al., 2007)

Intron 6 c.680+75G>A n/a n/a Rumsby et al. 2010

Intron 6 c.680+130C>T n/a n/a Rumsby et al. 2010

Intron 6 c.681-94G>A n/a major n/a Rumsby, unpublished

Exon 7 c.705G>A p.Thr235Thr major n/a rs35977912 (Coulter-Mackie et al., 2005)

Exon 7 c.742G>T p.Ala248Ser major 75% (Williams et al.,2009)

Intron 7 c.777-44A>G n/a n/a 0.71 rs12464426 (Monico et al., 2007)

Intron 7 c.777-45C>T n/a n/a 0.43 rs12478859

(Monico et al., 2007; Von Schnakenburg, 1998)

Exon 8 c.836T>C p.Ile279Thr major /minorb,e

100% on major. On same allele as known mutations (Coulter-Mackie. Et al., 2005. Monico. Et al., 2007)

In 1000 genomes

Rs140992177 MAF 0.0087/19

(Coulter-Mackie et al., 2005)

Exon 8 c.839C>T p.Ala280Val major 100%. On same Absent in 100 (Coulter-

allele as c.680+5G>C (Coulter-Mackie. Et al., 2005)

controls Mackie et al., 2005)

Intron 8 c.846+52G>A n/a major/minor n/a 0.63 rs12695032 (Monico et al., 2007)

Exon 9 c.865C>T p.Arg289Cys minor

No affect on activity or stability (C Tucker, personal communication 20/9/12)

(Rinat et al., 1999)

Exon 9 c.860_861delinsCG p.Ser287Thr

No effect on activity, trafficking or stability (Lage et al., 2014)

Frishberg et al., 2005

Exon 9 c.883G>A p.Ala295Thr major Predicted polymorphism

Williams and Rumsby unpublished

Intron 9 c.943-117C>T n/a major n/a Williams and Rumsby unpublished

Exon 10 c.976G>A p.Val326Ile major

96%. Found with p.Ala112Asp (Coulter-Mackie. Et al. 2003)

0.03 in South African

blacks: always found on African variant of minor

allele

(Coulter-Mackie et al.. 2003)

Exon 10 c.1020A>G p.Ile340Met minor (occasionally major)

76-117% (Lumb and Danpure. 2000)

0.15 rs4426527 (Purdue et al., 1992)

Intron 10 c.1072-91G>A n/a n/a (Monico et al., 2007)

Exon 11 c.1142G>A p.Arg381Lys Lys in other species. Benign by Sift and polyphen

Williams and Rumsby unpublished

Exon 11 c.1174C>T p.Leu392Leu major n/a (Williams et al.,2009)

3’-non coding region

c.*19G>A n/a major/minor n/a (Williams et al.,2009)

3’-non coding region

c.*41C>A n/a major/minor n/a 0.34-0.66 rs4273214

(von Schnakenburg and Rumsby, 1997)

3’-non coding region

c.*289C>A n/a major/minor n/a rs4344931 (Williams et al.,2009)

‡ found in conjunction with c.33dupC

Table 2: Variants of unknown significance (VUS) in the AGXT gene

Location Sequence variant Codon/effect Major (Pro11) or minor (Leu11)

haplotype

In vitro activity (% of normal) or how

proven

Frequency in controls

SNP database

Original Reference

Exon 1 c.28C>T p.Pro10Ser major

VUS 38% on minor 36% on major N.B. found in

conjunction with homozygosity for 33dupC. Does not

affect targeting

Williams et al.,2009)

Exon 2 c.296C>A p.Ser99Tyr major

VUS. Not fully conserved. On the same allele as the c.358+2G>T mutation

Absent in 80 controls (Williams et

al.,2009)

Exon 3 c.385G>C p.Asp129His major

VUS No obvious difference to wild type in yeast system (Lage et al., 2014)

Williams et al.,2009

Exon 5 c.557C>T§ p.Ala186Val major

VUS. SIFT & mutation taster predict functional change. In SNP database.

(Williams et al.,2009) Found in cis with 590G>A. Patient had PH2

Exon 8 c.837T>G p.Ile279Met unknown

VUS Normal activity and stability on minor allele (Lage et al., 2014). Prediction=disease

(Frishberg et al., 2005)

causing

Exon 8 c.845A>G p.Gln282Arg major

VUS. Prediction disease causing but normal activity and stability on minor allele (Lage et al., 2014)

Absent in 50 controls

(Williams et al.,2009)

Table 3: Missense and nonsense changes in the AGXT gene

Location Sequence variant Codon/effect

Major (Pro11) or

minor (Leu11)

haplotype

In vitro activity (% normal control) or how

proven Reference

Exon 1 c.2T>C p.Met1Thr unknown Absent in 50 controls (Yuen et al., 2004) Exon 1 c.3G>T p.Met1Ile major (Williams et al.,2009)

Exon 1 c.22G>C p.Val8Leu Prediction software; Liver bx proven Rumsby, unpublished

Exon 1 c.28C>T‡ p.Pro10Ser major

VUS 38% on minor 36% on major N.B. found in conjunction with homozygosity for 33dupC. Does not affect targeting

(Williams et al.,2009)

Exon 1 c.32C>G p.Pro11Arg major <2% on major and minor (Williams et al.,2009)

Exon 1 c.74T>G p.Leu25Arg unknown Reduced activity and stability on major and minor (Lage et al., 2014)

(Monico et al., 2007)

Exon 1 c.77T>C p.Leu26Pro major <1% on major and minora (Monico et al., 2007)

Exon 1 c.106C>T p.Arg36Cys minor

0% (Williams and Rumsby, 2007) Defective in activity only on major allele (Lage et al., 2014)

(Tintillier et al., 2004)

Exon 1 c.107G>A p.Arg36His major 8.5% on major. 5.4% on minor (Williams et al.,2009)

Exon 1 c.121G>A p.Gly41Arg major/minor 8% (Danpure et al., 1993) Exon 1 c.122G>A p.Gly41Glu major <1% (Williams and Rumsby, 2007)

Exon 1 c.122G>T p.Gly41Val major 18% on Major (Coulter-Mackie and Lian, 2006) (Pirulli et al., 1999)

Exon 1 c.125G>A p.Gly42Glu major ? (Williams et al.,2009)

Exon 1 c.130C>T p.Gln44X major n/a (Pirulli et al., 1999)

Exon 1 c.139G>A p.Gly47Arg minorg Absent in 50 controls; <3% activity (Pittman et al., 2012).

(Monico et al., 2007)

Exon 2 c.167T>A p.Ile56Asn major/minor Unstable on both polymorphic alleles (Lage et al, 2014)

(Williams et al.,2009)

Exon 2 c.175G>A p.Glu59Lys minor Prediction Rumsby, unpublished Exon 2 c.187G>C p.Gly63Arg major Fully conserved (Williams et al.,2009)

Exon 2 c.188G>A p.Gly63Asp Predicted probably damaging Hopp et al., 2015

Exon 2 c.198C>G p.Tyr66X major n/a (Purdue et al., 1991a) Exon 2 c.205C>T p.Gln69X major/minor (Williams et al.,2009)

Exon 2 c.209C>A p.Thr70Asn Biopsy proven. No other mutation found

Williams and Rumsby unpublished

Exon 2 c.242C>A p.Ser81X Li et al., BMC Nephrology 2014, 15:92

Exon 2 c.242C>T p.Ser81Leu major Absent in 142 controls; conserved in 17/22 orthologous sequences

(Williams et al.,2009)

Exon 2 c.244G>C p.Gly82Arg minor

2.7% (Lumb and Danpure, 2000) Impaired activity on both alleles, unstable on minor (Lage et al.,2014)

(Van Woerden et al., 2004)

Exon 2 c.245G>A p.Gly82Glu major <2% (Purdue et al., 1992)

Exon 2 c.248A>G p.His83Arg minor

0% Impaired activity on both alleles, unstable on minor (Lage et al.,2014)

(Williams et al.,2009)

Exon 2 c.254C>A p.Ala85Asp Biopsy proven Williams and Rumsby unpublished

Exon 2 c.283G>A p.Glu95Lys minor <5% Decreased activity and stability on both alleles

(Williams et al.,2009)

(Lage et al., 2014) Exon 2 c.292G>C p.Asp98His Prediction Hopp et al., 2015

Exon 2 c.302T>C p.Leu101Pro major <1% on major and minor

Predominantly Asian ethnicity

(Williams et al.,2009)

Exon 2 c.322T>C p.Trp108Arg minor

3.5% on minor (Coulter-Mackie and Lian, 2006) Impaired activity on both alleles, unstable on minor (Lage et al.,2014)

(Von Schnakenburg and Rumsby, 1998)

Exon 2 c.323G>A p.Trp108X major Mutation Taster predicts disease causing (Williams et al.,2009)

Exon 2 c.324G>T p.Trp108Cys major Mutation Taster predicts disease causing

Williams and Rumsby, unpublished

Exon 2 c.326G>T p.Gly109Val minor Reduced activity and stability on major and minor (Lage et al., 2014)

(Williams et al.,2009)

Exon 2 c.331C>T p.Arg111X major n/a (Coulter-Mackie et al., 2004)

Exon 2 c.332G>A p.Arg111Gln unknown Reduced activity and stability on major and minor (Lage et al., 2014)

(Williams et al.,2009)

Exon 2 c.335C>A* p.Ala112Asp major 5% on major (Coulter-Mackie et al., 2003); *erroneously reported as 336C>A

Exon 2 c.346G>A p.Gly116Arg major <1% on major and minora (Pirulli et al., 1999)

Exon 2 c.349G>T p.Glu117X unknown Nonsense mutation Williams and Rumsby, unpublished

Exon 2 c.352C>T p.Arg118Cys minor Prediction programmes Negligible AGT activity in liver biopsy

Rumsby, unpublished

Exon 2 c.353G>A p.Arg118His minor Prediction programmes Williams and Rumsby, unpublished

Exon 3 c.364C>T p.Arg122X minor n/a (Williams et al.,2009)

Exon 3 c.371A>C p.His124Pro major ‘possibly damaging’ on Polyphen. Dx confirmed

Williams and Rumsby, unpublished

on liver bx. Exon 3 c.409C>T p.Gln137X major n/a (Williams et al.,2009)

Exon 3 c.423G>T p.Glu141Asp, may also affect splicing major

100% on minor; 50% on majora. ?affects splicing (last nucleotide in exon). Found in biopsy proven patient

(Von Schnakenburg, 1998)

Exon 4 c.449T>C p.Leu150Pro minor <1% on major and minor (Williams and Rumsby, 2007) Exon 4 c.454T>A p.Phe152Ile minor <2% (Danpure et al., 1993)

Exon 4 c.457T>G p.Leu153Val major

Normal activity on minor allele. Approx 50% reduction in stability (Lage et al., 2014)

(Van Woerden et al., 2004)

Exon 4 c.466G>A p.Gly156Arg major <1% on major and minor (Williams and Rumsby, 2007)

(Pirulli et al., 1999; Rinat et al., 1999)

Exon 4 c.473C>T p.Ser158Leu major <1% on major and minor (Williams and Rumsby, 2007)

(Monico et al., 2005)

Exon 4 c.473C>A p.Ser158X major Nonsense mutation (Williams et al.,2009)

Exon 4 c.481G>T p.Gly161Cys minor

<1% on minor; 9% on major (Williams and Rumsby, 2007) Affects activity and stability on major and minor (Lage et al., 2014)

(Williams and Rumsby, 2007)

Exon 4 c.481G>A p.Gly161Ser minor

<1% on minor;15% on major (Williams and Rumsby, 2007).

Reduce expression and half-life of AGT; aggregation (Oppici et

(Williams and Rumsby, 2007)

al., 2013)

Decreased stability on major and minor (Lage et al., 2014)

Exon 4 c.481G>C p.Gly161Arg major

6.2% on major Affects activity and stability on major and minor alleles (Lage et al.,2014)

(Coulter-Mackie et al., 2005)

Exon 4 c.482G>A p.Gly161Asp major Hoyer-Kuhn et al. 2014

Exon 4 c.497T>C p.Leu166Pro minor

<1% on minor;16% on major (Williams and Rumsby, 2007) Affects activity and stability on both major and minor but greater affect on minor (Lage et al., 2014)

(Williams and Rumsby, 2007)

Exon 4 c.508G>A p.Gly170Arg minor 40% on minor; 68% on major (Lumb and Danpure, 2000)

(Purdue et al., 1990)

Exon 4 c.518G>A p.Cys173Tyr major <1% on major and minor (Williams and Rumsby, 2007)

(Von Schnakenburg and Rumsby, 1998)

Exon 4 c.519C>A p.Cys173X major n/a (Van Woerden et al., 2004)

Exon 5 c.533G>A p.Cys178Tyr major Sift + polyphen predict pathological. Biopsy proven

Williams and Rumsby, unpublished

Exon 5 c.547G>A p.Asp183Asn major 2.9% on major (Coulter-

Mackie and Lian, 2006) (Basmaison et al., 2000)

Exon 5 c.560C>T p.Ser187Phe major 2.8% on major (Coulter-Mackie and Lian, 2006) (Minatogawa, et al., 1992)

Exon 5 c.560C>A p.Ser187Tyr prediction Hopp et al., 2015

Exon 5 c.568G>A p.Gly190Arg major/minor <1% on major and minora

(Rinat et al., 1999; Von Schnakenburg and Rumsby, 1998)

Exon 5 c.583A>C p.Met195Leu minor

Affects activity and stability on major and minor alleles (Lage et al. 2014)

(Williams et al.,2009)

Exon 5 c.584T>G p.Met195Arg minor

Reduced activity on major and minor in yeast expression system (Lage et al., 2014)

(Frishberg et al., 2005)

Exon 5 c.595G>A p.Gly199Ser; probable splice change major

In silico prediction. Tracks with disease in family

Rumsby et al., unpublished

Exon6 c.603C>A p.Asp201Glu major <5% on major and <10% on minor (Lage et al., 2014)

(Monico et al., 2005)

Exon 6 c.605T>A p.Ile202Asn Prediction: Sift and Polyphen

Li et al., BMC Nephrology 2014, 15:92

Exon 6 c.612C>A p.Tyr204X major n/a (Monico et al., 2005)

Exon 6 c.613T>C p.Ser205Pro major 2.5% on major (Coulter-Mackie and Lian, 2006) (Nishiyama et al., 1991)

Exon 6 c.614C>T p.Ser205Leu major <3% on major and minor (Williams et al.,2009) Exon 6 c.614C>A p.Ser205X major n/a (Williams et al.,2009)

Exon 6 c.628G>C p.Ala210Pro No other mutation found (liver bx proven) Aquaviva, unpublished

Exon 6 c.646G>A p.Gly216Arg major Absent in 50 controls <3% (this papera) (Monico et al., 2007)

Exon 6 c.653C>T p.Ser218Leu major 10% on Major (Coulter-Mackie et al., 2005) Exon 6 c.661T>C p.Ser221Pro major <3% on major and minor (Williams et al.,2009)

Exon 7 c.697C>T p.Arg233Cys minor <1% on minor; 14% on Major (Williams and Rumsby, 2007)

(von Schnakenburg and Rumsby, 1997)

Exon 7 c.698G>A p.Arg233His minor <1% on minor; 14% on Major (Williams and Rumsby, 2007)

(von Schnakenburg and Rumsby, 1997)

Exon 7 c.698G>T p.Arg233Leu unknown Absent in 50 controls (Monico et al., 2005)

Exon 7 c.727G>C p.Asp243His unknown

<5% activity on minor, approx 50% on major. Unstable on both alleles (Laga et al., 2014)

(Frishberg et al., 2005)

Exon 7 c.731T>C p.Ile244Thr minor (occasionally major)

<1% on minor; 50% on major (Lumb and Danpure, 2000)

(von Schnakenburg and Rumsby, 1997)

Exon 7 c.737G>A p.Trp246X minor Nonsense mutation (Monico et al., 2007; Williams and Rumsby, 2007)

Exon 7 c.738G>A p.Trp246X major Nonsense mutation (von Schnakenburg and Rumsby, 1997)

Exon 7 c.753G>A p.Trp251X major Nonsense mutation (Coulter-Mackie, et al., 2004)

Exon 7 c.757T>C p.Cys253Arg minor

<1% on minor; 7% on Major (Williams and Rumsby, 2007) Decreased activity and stability on both alleles (Lage et al., 2014)

(Monico et al., 2005; Williams and Rumsby, 2007)

Exon 8 c.783T>A p.His261Gln unknown <3% (Pittman et al., 2012) (Monico et al., 2007)

Exon 8 c.779A>G p.Tyr260Cys Prediction Hopp et al., 2015 Exon 8 c.781C>G p.His261Asp Prediction Hopp et al., 2015

Exon 8 c.806T>C p.Leu269Pro major

<5% on major and minor alleles and affects stability on both alleles (Lage et al., 2014)

(Williams et al.,2009)

Exon 8 c.815T>C p.Leu272Pro Prediction Hopp et al., 2015

Exon 8 c.822G>C p.Glu274Asp minor

<3% (Pittman et al., 2012) Normal activity on major (Lage et al., 2014)

(Williams et al.,2009)

Exon 8 c.823A>C p.Ser275Arg major/minor <3% on both majorand minor allele (Pittman et al., 2012)

(Williams et al.,2009)

Exon 8 c.837T>G p.Ile279Met Exon 8 c.844C>T p.Gln282X unknown Nonsense mutation (Yuen, et al., 2004)

Exon 8 c.846G>C p.Gln282His major Prediction disease causing. Found in biopsy-proven PH1

(Williams et al.,2009)

Exon 9 c.851T>C p.Leu284Pro minor

Reduced activity and stability on both major and minor (Lage et al., 2014)

(Williams et al.,2009)

Exon 9 c.853G>T p.Glu285X major Nonsense mutation (Williams et al.,2009)

Exon 9 c.866G>A p.Arg289His major Not tested. R conserved in mammals (except rabbit.

Williams and Rumsby unpublished

Exon 9 c.891T>G p.Tyr297X major Nonsense mutation (Williams et al.,2009)

Exon 9 C.893T>C p.Leu298Pro§ minor

Absent in 100 controls; Destabilising (C Tucker, personal communication 20/9/12 and Lage et al., 2014) Variant in cis with p.Arg289Cys

(Rinat et al., 1999)

Exon 9 c.907C>T p.Gln303X unknown Nonsense mutation (Monico et al., 2007)

Exon 9 c.922C>T p.Gln308X major Nonsense mutation Williams and Rumsby unpublished

Exon 10 c.947T>C p.Leu316Pro Biopsy proven. No other mutation found

Williams and Rumsby, unpublished

Exon 10 c.949C>T p.Arg317Trp Prediction Hopp et al., 2015

Exon 10 c.956C>T p.Pro319Leu unknown Absent in 50 controls; <5% on minor allele, decreased stability on

(Monico, et al., 2007)

both alleles (Lage et al., 2014)

Exon 10 c.996G>A p.Trp332X Nonsense mutation Biopsy proven PH1

Williams and Rumsby, unpublished

Exon 10 c.997A>T p.Arg333X major Nonsense mutation (Rinat et al., 1999)

Exon 10 c.1007T>A p.Val336Asp minor 5.2% on minor; 22.4% on major (Coulter-Mackie and Lian, 2008)

(Van Woerden et al., 2004) originally described in cis with p.Gly170Arg; since found on its own (GR)

Exon 10 c.1014C>G p.Tyr338X Nonsense mutation Williams and Rumsby, unpublished

Exon 10 c.1045G>A p.Gly349Ser Found in biopsy proven PH1

Williams and Rumsby, unpublished

Exon 10 c.1049G>A p.Gly350Asp minor 2.9% on major, 7.6% on minor (this papera)

(Von Schnakenburg and Rumsby, 1998)

Exon 10 c.1076T>C p.Leu359Pro major

L conserved in middle of beta sheet. Reduced activity and stability on major and minor alleles (Lage et al., 2014)

Williams and Rumsby unpublished

Exon 11 c.1078C>T p.Arg360Trp Prediction Hopp et al., 2015

Exon 11 c.1079G>A p.Arg360Gln major <1% on major and minora (Williams et al.,2009)

Exon 11 c.1084G>A p.Gly362Ser Prediction Hopp et al., 2015

Exon 11 c.1102G>A p.Ala368Thr minor

Affects activity, stability and growth on minor allele. Lesser affect on major allele (Laga et al.,2014)

(Williams et al.,2009)

Exon 11 c.1148C>A p.Ala383Asp major Prediction programmes Willliams and Rumsby unpublished

Exon 11 c.1151T>C p.Leu384Pro major Reduced activity on major and minor (Lage et al., 2014)

(Williams et al.,2009)

Table 4: Splice site mutations in the AGXT gene

Mutation Effect Reference Splice donor

Intron 2 c.358+1G>T (Van Woerden et al., 2004) Intron 2 c.358+2T>G (Williams et al.,2009) Intron 6 c.680+1G>C (Williams et al.,2009) Intron 6 c.680+1G>A (Williams et al.,2009) Intron 6 c.680+2T>A Intron 6 c.680+5G>C (Coulter-Mackie, et al., 2005)

Intron 7 c.776+1G>A

p.Met259fs inclusion of 24 nucleotides (Williams and

Rumsby, 2007)

(Monico et al., 2007; Williams and Rumsby, 2007)

Intron 7 c.776+1G>C (Monico et al., 2007) Intron 8 c.846+1G>T (Coulter-Mackie et al., 2004) Intron 8 c.846+1G>A (Williams et al.,2009) Intron 9 c.942+1G>T (Monico et al., 2005) Intron 10 c.1071+1G>A (Williams et al.,2009)

Splice acceptor Intron 1 c.166-1G>A (Van Woerden et al., 2004)

Intron 3 c.424-2A>G p.Gly_142Gln145del

Loss of 12 nucleotides at beginning of exon 4 (Williams and Rumsby, 2007)

(Williams and Rumsby, 2007)

Intron 4 c.525-1G>A (Basmaison et al., 2000) Intron 5 c.595+1G>T Hopp et al., 2015 Intron 5 c.596-2A>G Williams and Rumsby, unpublished Intron 7 c.777-1G>C (Coulter-Mackie et al., 2004) Intron 7 c.777-2A>G Williams and Rumsby, unpublished Intron 8 c.846+1G>T Halbritter et al., 2015 Intron 8 c.847-1G>C (Basmaison et al., 2000) Intron 8 c.847-3C>G (Basmaison et al., 2000) Intron 9 c.943-1G>T (Williams et al.,2009)

Intron 9 c.943-1G>A Clifford-Mobley & Rumsby unpublished

Table 5: Deletion/insertion mutations in the AGXT gene

Location Mutation Codon Major or

minor allele

Confirmation Original reference

Exon 1 c.2_3delinsAT p.Met1Asn (activity <1%) major (Williams and

Rumsby, 2007)

Exon 1 c.33delC p.Lys12fs major (Pirulli et al., 1999)

Exon 1 c.32_33delCC p.Pro11fs major (Williams and

Rumsby, 2007)

Exon 1 c.33dupC (formerly c.33_34insC) p.Lys12fs major (Pirulli et al.,

1999)

Exon 1 c.34_35dupAA p.Lys12fs Hopp et al., 2015

Exon 1 c.83delC p.Pro28fs major (Williams et al.,2009)

Exon 1 c.116_117dupCA p.Ala40fs major (Coulter-

Mackie et al., 2005)

Exon 1 c.126delG p.Leu43fs major (Williams and

Rumsby, 2007)

Exon 1 c.126dupG p.Leu43fs Hopp et al., 2015

Exon 2 c.215dupA p.Asn72fs Williams and

Rumsby, unpublished

Exon 2 c.221_227dupTCACACT p.Val77fs major (Basmaison et al., 2000)

Exon 2 c.276delT p.Asn92fs major (Williams et al.,2009)

Exon 2 c.283_285dupGAG p.Glu95dup major (Pirulli et al., 1999)

Exon 2 c.299_307dupTCCTGGTTG p.Val102_Gly103ins Val, Leu,Val Hopp et al, 2015

Exon 2 c.[299_307dup;c.308G>A] p.[Val102insValLeuVal;Gly103Glu] unknown (Monico, et al., 2007)

Exon 2 c.327delG p.Gln110fs major (Coulter-

Mackie et al., 2005)

Exon 3 c.359-4_379del Rumsby, unpublished

Exon 3 c.402C>G p.Tyr134* Hopp et al., 2015

Exon 3 c.416_418delTGG p.Val139del majorb (Monico et al., 2007)

Exon 4 c.447_454delGCTGCTGT p.Leu151fs major (Williams and

Rumsby, 2007)

Exon 4 c.445delG p.Val149fs major (Williams et al.,2009)

Exon 4 c.460delA p.Thr154fs major (Williams et al.,2009)

Exon 4 c.485delT p.(Val162Glyfs*50) minor Rumsby unpublished

Exon 4 c.496delG p.Glu157fs Hopp et al., 2015

Exon 4 c.519_520delinsGA p.[Cys173Trp;His174Asn] major <10% AGT activity in liver bx

Williams and Rumsby, unpublished

Exon 5 c.557_562delinsATCGGT p.[Ala186Asp;Phe187Arg] minor Williams and

Rumsby, unpublished

Exon 5 c.560_561insGGT p.Ser187_Leu188insVal‡

‡ aa inserted incorrectly reported as gly.

Hopp et al., 2015

Exon 5 c.570delG p.Thr191fs major (Coulter-

Mackie et al., 2004)

Exon 5 c.577delC p.Leu193fs major Rumsby, unpublished

Exon 5 c.577dupC p.Leu193fs major (Williams et al.,2009)

Exon 6 c.642_645delTCCA p.Pro215fs major (Williams et al.,2009)

Exon 6 c.661_663delTCC p.Ser221del

Exon6/Intron 6 c.679_680+2delAAgt ?Missplicing or p.Lys227Glu major

(Coulter-Mackie, et al., 2001)

Exon 7 c.680+480_c.776+69del732insTGAGA NC_000002.12:g.240874542_240875273del732insTGAGA

p.Lys228_Met259del32 (in frame deletion of exon 7) (Robbiano et

al., 2010)

Exon 7 c.725dupT p.Asp243fs major (Williams and

Rumsby, 2007)

Exon 7 c.744delC p.Asp249fs major (Coulter-

Mackie et al., 2004)

Exon 7 c.751_752delinsAA p.Trp251Lys (peroxisomal and cytosolic distribution) Kawai et al.,

2012

Exon 8 c.798_802delinsACAATCTCAG p.Ile267fs major (von

Schnakenburg et al., 1998)

Exon 8 c.823_824dupAG p.Ser275fs unknown (Yuen, et al., 2004)

Exon8 c.829_830insA,c.830C>A p.Ala277fs minor Williams and

Rumsby, unpublished

Exon 8 c.832delC p.Leu278fs Hopp et al., 2015

Exon 8 c.834delC p.Ile279fs minor (Williams et al.,2009)

Exon 9 c.846+646_c.942+139del1121 NC_000002.12:g.240876650_240877771del1122 deletion exon 9 major

(Coulter-Mackie et al., 2005)

Exon 9 c.860_861delinsCG p.Ser287Thr unknown (Frishberg et al., 2005)

Exon 9 c.886_888delGCG Ala296del major (Von

Schnakenburg and Rumsby,1998)

Exon 9 c.919delC p.Leu307fs major (Williams et al.,2009)

Exon 10 c.959_960delCA p.Thr320fs Williams and

Rumsby unpublished

Exon 10 c.971-972delTG p.Val324fs major (Williams et al.,2009)

Exon 10 c.973delG p.Ala325fs

Exon 10 c.976delG p.Val326fs major (Pirulli et al., 1999)

Exon 10 c.983_988delCTGGCT p.Ala328_Tyr330delinsAsp major (Coulter-

Mackie et al., 2004)

Exon 11 c.1110_1111delCG p.Asn372fs minor Williams and

Rumsby, unpublished

Exon 11 c.1125_1126delCG p.Val376fs major (Coulter-

Mackie et al., 2001)

Exon 11_3’UTRdel

truncating

(Monico et al., 2007)

Ex1_5del 5-6 kb deletion (Coulter-

Mackie et al., 2001)

Ex1_7del 10 kb deletion (Nogueira et al., 2000)

Ex5_11del >6kb deletion (Williams et al.,2009)

g.238094544-telomere Major deletion including HDAC4 Tammachote

et al., 2012

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