ALANINE:GLYOXYLATE AMINOTRANSFERASE (AGXT) GENE (PRIMARY HYPEROXALURIA TYPE 1) MUTATION DATA BASE

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1 ALANINE:GLYOXYLATE AMINOTRANSFERASE (AGXT) GENE (PRIMARY HYPEROXALURIA TYPE 1) REFERENCE SEQUENCES: c.dna: NM_ g.dna: NG_ MUTATION DATA BASE Nomenclature: HGVS guidelines ( 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.

2 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 Exon 1 c.26c>a p.thr9asn major Exon 1 c.27c>a p.thr9thr major n/a Exon 1 c.32c>t p.pro11leu minor Exon 1 c.32c>a p.pro11his major 55% Exon 1 c.35a>g p.lys12arg major In vitro activity (% of normal) or how proven 138% (Williams and 64% (Lumb and Danpure, 2000). Defines the AGXT minor allele Sift predicts tolerated Frequency in controls 0.01 SNP database 0.20 rs Does not track with disease Exon 1 c.65a>g p.asn22ser major 0.05 rs Intron 1 c a>g n/a minor (the A variant occasionally on minor) Intron 1 c c>t n/a minor n/a Intron 1 c c>t n/a minor n/a Intron 1 c _165+92dup74 n/a minor (occasionally major) Intron 1 c t>a n/a minor n/a n/a n/a 0.24 Original Reference (Frishberg et al., 2005; Monico et al., 2005) (Purdue et al., 1990) Williams and (Purdue et al., 1991a)

3 Intron 1 c a>c n/a minor n/a Intron 1 c c>t n/a minor n/a Intron 1 c t>c n/a minor n/a Intron 1 c c>t n/a major n/a Exon 2 c.264c>t p.ala88ala minor n/a 0.21 rs Intron 2 c c>t n/a minor n/a 0.20 rs Intron 2 c _358+64del9 n/a major n/a Intron 3 c c>t n/a n/a Intron 3 c a>c n/a major n/a Intron 3 c t>g n/a n/a Intron 3 c _13dupc n/a major n/a Intron 3 c g>a n/a major n/a Exon 4 c.489g>a p.leu163leu n/a Intron 4 c c>t n/a n/a 0.29 Intron 4 VNTR (29/32)n n/a Exon 5 c.590g>a p.arg197gln major minor/major. Minor typically with largest repeat n/a Mutation taster predicts benign. (Danpure et al., 1994a) (Von Schnakenburg, 1998) Rumsby et al Rumsby et al (Monico et al., (Danpure et al., 1994b) Incorrectly

4 Exon 6 c.654g>a p.ser218ser major n/a 0.06 rs Intron 6 c c>t n/a minor n/a 0.18 rs Intron 6 c g>a n/a n/a Intron 6 c c>t n/a n/a Intron 6 c g>a n/a major n/a Exon 7 c.705g>a p.thr235thr major n/a rs Exon 7 c.742g>t p.ala248ser major 75% Intron 7 c a>g n/a n/a 0.71 rs Intron 7 c c>t n/a n/a 0.43 rs Exon 8 c.836t>c p.ile279thr major /minor b,e 100% on major. On same allele as known mutations (Coulter-Mackie. Et al., Monico. Et al., In 1000 genomes Rs MAF /19 reported as G>T. Found in cis with c.557c>t in PH2 patient (Monico et al., 2007; Von Schnakenburg. 1998) (Monico et al., Rumsby et al Rumsby et al (Coulter- Mackie et al., 2005) (Monico et al., (Monico et al., 2007; Von Schnakenburg, 1998) (Coulter- Mackie et al., 2005) Exon 8 c.839c>t p.ala280val major 100%. On same Absent in 100 (Coulter-

5 allele as c.680+5g>c (Coulter-Mackie. Et al., 2005) controls Intron 8 c g>a n/a major/minor n/a 0.63 rs Exon 9 c.865c>t p.arg289cys minor Exon 9 c.860_861delinscg p.ser287thr Exon 9 c.883g>a p.ala295thr major Intron 9 c c>t n/a major n/a Exon 10 c.976g>a p.val326ile major Exon 10 c.1020a>g p.ile340met minor (occasionally major) Intron 10 c g>a n/a n/a Exon 11 c.1142g>a p.arg381lys No affect on activity or stability (C Tucker, personal communication 20/9/12) No effect on activity, trafficking or stability (Lage et al., 2014) Predicted polymorphism 96%. Found with p.ala112asp (Coulter-Mackie. Et al. 2003) % (Lumb and Danpure. 2000) Lys in other species. Benign by Sift and polyphen 0.03 in South African blacks: always found on African variant of minor allele 0.15 rs Mackie et al., 2005) (Monico et al., (Rinat et al., 1999) Frishberg et al., 2005 Williams and Rumsby Williams and Rumsby (Coulter- Mackie et al ) (Purdue et al., 1992) (Monico et al., Williams and Rumsby

6 Exon 11 c.1174c>t p.leu392leu major n/a 3 -non coding region 3 -non coding region c.*19g>a n/a major/minor n/a c.*41c>a n/a major/minor n/a rs non coding region c.*289c>a n/a major/minor n/a rs found in conjunction with c.33dupc (von Schnakenburg and 1997)

7 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 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 Exon 2 c.296c>a p.ser99tyr major Exon 3 c.385g>c p.asp129his major Exon 5 c.557c>t p.ala186val major Exon 8 c.837t>g p.ile279met unknown VUS. Not fully conserved. On the same allele as the c.358+2g>t mutation VUS No obvious difference to wild type in yeast system (Lage et al., 2014) VUS. SIFT & mutation taster predict functional change. In SNP database. VUS Normal activity and stability on minor allele (Lage et al., 2014). Prediction=disease Frequency in controls Absent in 80 controls SNP database Original Reference Williams et Williams et al.,2009 Found in cis with 590G>A. Patient had PH2 (Frishberg et al., 2005)

8 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

9 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 Exon 1 c.22g>c p.val8leu Prediction software; Liver bx proven VUS 38% on minor 36% on major Exon 1 c.28c>t p.pro10ser major N.B. found in conjunction with homozygosity for 33dupC. Does not affect targeting Exon 1 c.32c>g p.pro11arg major <2% on major and minor Exon 1 c.74t>g p.leu25arg unknown Reduced activity and stability on major and (Monico et al., minor (Lage et al., 2014) Exon 1 c.77t>c p.leu26pro major <1% on major and minor a (Monico et al., Exon 1 c.106c>t p.arg36cys minor 0% (Williams and Defective in activity only (Tintillier et al., 2004) on major allele (Lage et al., 2014) Exon 1 c.107g>a p.arg36his major 8.5% on major. 5.4% on minor 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 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?

10 Exon 1 c.130c>t p.gln44x major n/a (Pirulli et al., 1999) Exon 1 c.139g>a p.gly47arg minor g <3% activity (Pittman et (Monico et al., Absent in 50 controls; al., 2012). Exon 2 c.167t>a p.ile56asn major/minor Unstable on both polymorphic alleles (Lage et al, 2014) Exon 2 c.175g>a p.glu59lys minor Prediction Exon 2 c.187g>c p.gly63arg major Fully conserved 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 Exon 2 c.209c>a p.thr70asn Biopsy proven. No other Williams and Rumsby mutation found Exon 2 c.242c>a p.ser81x Exon 2 c.242c>t p.ser81leu major Exon 2 c.244g>c p.gly82arg minor Absent in 142 controls; conserved in 17/22 orthologous sequences 2.7% (Lumb and Danpure, 2000) Impaired activity on both alleles, unstable on minor (Lage et al.,2014) Li et al., BMC Nephrology 2014, 15:92 (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) Exon 2 c.254c>a p.ala85asp Biopsy proven <5% Exon 2 c.283g>a p.glu95lys minor Decreased activity and stability on both alleles Williams and Rumsby

11 (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 3.5% on minor (Coulter- Exon 2 c.322t>c p.trp108arg minor Mackie and Lian, 2006) (Von Schnakenburg and Impaired activity on both 1998) alleles, unstable on minor (Lage et al.,2014) Exon 2 c.323g>a p.trp108x major Mutation Taster predicts disease causing Exon 2 c.324g>t p.trp108cys major Mutation Taster predicts Williams and disease causing Reduced activity and Exon 2 c.326g>t p.gly109val minor stability on major and minor (Lage et al., 2014) 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) Exon 2 c.335c>a* p.ala112asp major 5% on major Exon 2 c.346g>a p.gly116arg major (Coulter-Mackie et al., 2003); *erroneously reported as 336C>A <1% on major and minor a (Pirulli et al., 1999) Williams and Exon 2 c.349g>t p.glu117x unknown Nonsense mutation Prediction programmes Exon 2 c.352c>t p.arg118cys minor Negligible AGT activity in liver biopsy Williams and Exon 2 c.353g>a p.arg118his minor Prediction programmes Exon 3 c.364c>t p.arg122x minor n/a Exon 3 c.371a>c p.his124pro major possibly damaging on Williams and Polyphen. Dx confirmed

12 on liver bx. Exon 3 c.409c>t p.gln137x major n/a 100% on minor; 50% on Exon 3 c.423g>t major a.?affects splicing p.glu141asp, may also major (last nucleotide in exon). affect splicing Found in biopsy proven patient (Von Schnakenburg, 1998) Exon 4 c.449t>c p.leu150pro minor <1% on major and minor (Williams and 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 (Pirulli et al., 1999; Rinat et al., (Williams and 1999) <1% on major and minor Exon 4 c.473c>t p.ser158leu major (Williams and (Monico et al., 2005) Exon 4 c.473c>a p.ser158x major Nonsense mutation Exon 4 c.481g>t p.gly161cys minor <1% on minor; 9% on major (Williams and Affects activity and stability on major and minor (Lage et al., 2014) (Williams and Exon 4 c.481g>a p.gly161ser minor <1% on minor;15% on major (Williams and. Reduce expression and half-life of AGT; aggregation (Oppici et (Williams and

13 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 (Coulter-Mackie et al., 2005) minor alleles (Lage et al.,2014) Exon 4 c.482g>a p.gly161asp major Hoyer-Kuhn et al Exon 4 c.497t>c p.leu166pro minor <1% on minor;16% on major (Williams and Affects activity and stability on both major (Williams and and minor but greater affect on minor (Lage et al., 2014) 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 (Von Schnakenburg and 1998) Exon 4 c.519c>a p.cys173x major n/a (Van Woerden et al., 2004) Exon 5 c.533g>a p.cys178tyr major Exon 5 c.547g>a p.asp183asn major Exon 5 c.560c>t p.ser187phe major Sift + polyphen predict pathological. Biopsy proven 2.9% on major (Coulter- Mackie and Lian, 2006) 2.8% on major (Coulter- Mackie and Lian, 2006) Williams and (Basmaison et al., 2000) (Minatogawa, et al., 1992) Exon 5 c.560c>a p.ser187tyr prediction Hopp et al., 2015

14 Exon 5 c.568g>a p.gly190arg major/minor Exon 5 c.583a>c p.met195leu minor Exon 5 c.584t>g p.met195arg minor Exon 5 c.595g>a p.gly199ser; probable splice change major <1% on major and minor a Affects activity and stability on major and minor alleles (Lage et al. 2014) Reduced activity on major and minor in yeast expression system (Lage et al., 2014) In silico prediction. Tracks with disease in family (Rinat et al., 1999; Von Schnakenburg and 1998) (Frishberg et al., 2005) Rumsby et al., Exon6 c.603c>a p.asp201glu major Exon 6 c.605t>a p.ile202asn <5% on major and <10% on minor (Lage et al., 2014) Prediction: Sift and Polyphen (Monico et al., 2005) 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 Exon 6 c.614c>a p.ser205x major n/a Exon 6 c.628g>c p.ala210pro No other mutation found (liver bx proven) Aquaviva, Exon 6 c.646g>a p.gly216arg major Absent in 50 controls <3% (this paper a ) (Monico et al., 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 Exon 7 c.697c>t p.arg233cys minor <1% on minor; 14% on Major (Williams and (von Schnakenburg and 1997)

15 Exon 7 c.698g>a p.arg233his minor <1% on minor; 14% on Major (Williams and (von Schnakenburg and 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 <1% on minor; 50% on (von Schnakenburg and (occasionally major (Lumb and 1997) major) Danpure, 2000) (Monico et al., 2007; Williams Exon 7 c.737g>a p.trp246x minor Nonsense mutation and (von Schnakenburg and Exon 7 c.738g>a p.trp246x major Nonsense mutation 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 Decreased activity and stability on both alleles (Lage et al., 2014) (Monico et al., 2005; Williams and Exon 8 c.783t>a p.his261gln unknown <3% (Pittman et al., 2012) (Monico et al., 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) 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)

16 Exon 8 c.823a>c p.ser275arg major/minor <3% on both majorand minor allele (Pittman et al., 2012) 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 Exon 9 c.851t>c p.leu284pro minor Reduced activity and stability on both major and minor (Lage et al., 2014) Exon 9 c.853g>t p.glu285x major Nonsense mutation Exon 9 c.866g>a p.arg289his major Not tested. R conserved in mammals (except rabbit. Williams and Rumsby Exon 9 c.891t>g p.tyr297x major Nonsense mutation Exon 9 C.893T>C p.leu298pro minor Absent in 100 controls; Destabilising (C Tucker, personal communication 20/9/12 and Lage et al., (Rinat et al., 1999) 2014) Variant in cis with p.arg289cys Exon 9 c.907c>t p.gln303x unknown Nonsense mutation (Monico et al., Williams and Rumsby Exon 9 c.922c>t p.gln308x major Nonsense mutation Exon 10 c.947t>c p.leu316pro Biopsy proven. No other Williams and mutation found 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.,

17 both alleles (Lage et al., 2014) Exon 10 c.996g>a p.trp332x Nonsense mutation Williams and Biopsy proven PH1 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% (Van Woerden et al., 2004) originally described in cis with on major (Coulter- p.gly170arg; since found on its Mackie and Lian, 2008) own (GR) Williams and Exon 10 c.1014c>g p.tyr338x Nonsense mutation Exon 10 c.1045g>a p.gly349ser Found in biopsy proven Williams and PH1 Exon 10 c.1049g>a p.gly350asp minor 2.9% on major, 7.6% on (Von Schnakenburg and minor (this paper a ) 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 Exon 11 c.1078c>t p.arg360trp Prediction Hopp et al., 2015 Exon 11 c.1079g>a p.arg360gln major <1% on major and minor a 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) Exon 11 c.1148c>a p.ala383asp major Prediction programmes Reduced activity on Exon 11 c.1151t>c p.leu384pro major major and minor (Lage et al., 2014) Willliams and Rumsby

18 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 Intron 6 c.680+1g>c Intron 6 c.680+1g>a 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 (Monico et al., 2007; Williams and Intron 7 c.776+1g>c (Monico et al., Intron 8 c.846+1g>t (Coulter-Mackie et al., 2004) Intron 8 c.846+1g>a Intron 9 c.942+1g>t (Monico et al., 2005) Intron 10 c g>a 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 (Williams and exon 4 (Williams and 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 Intron 7 c.777-1g>c (Coulter-Mackie et al., 2004) Intron 7 c.777-2a>g Williams and 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 Clifford-Mobley & Rumsby Intron 9 c.943-1g>a

19 Table 5: Deletion/insertion mutations in the AGXT gene Location Mutation Codon Major or minor allele Exon 1 c.2_3delinsat p.met1asn (activity <1%) major Exon 1 c.33delc p.lys12fs major Exon 1 c.32_33delcc p.pro11fs major Exon 1 c.33dupc (formerly c.33_34insc) p.lys12fs Exon 1 c.34_35dupaa p.lys12fs Exon 1 c.83delc p.pro28fs major Exon 1 c.116_117dupca p.ala40fs major Exon 1 c.126delg p.leu43fs major major Confirmation Original reference (Williams and (Pirulli et al., 1999) (Williams and (Pirulli et al., 1999) Hopp et al., 2015 (Coulter- Mackie et al., 2005) (Williams and Exon 1 c.126dupg p.leu43fs Hopp et al., 2015 Williams and Exon 2 c.215dupa p.asn72fs Exon 2 c.221_227duptcacact p.val77fs major Exon 2 c.276delt p.asn92fs major Exon 2 c.283_285dupgag p.glu95dup major Exon 2 c.299_307duptcctggttg p.val102_gly103ins Val, Leu,Val Exon 2 c.[299_307dup;c.308g>a] p.[val102insvalleuval;gly103glu] unknown (Basmaison et al., 2000) (Pirulli et al., 1999) Hopp et al, 2015 (Monico, et al.,

20 Exon 2 c.327delg p.gln110fs major (Coulter- Mackie et al., 2005) Exon 3 c.359-4_379del Hopp et al., Exon 3 c.402c>g p.tyr134* 2015 Exon 3 c.416_418deltgg p.val139del major b (Monico et al., Exon 4 c.447_454delgctgctgt p.leu151fs major Exon 4 c.445delg p.val149fs major Exon 4 c.460dela p.thr154fs major Exon 4 c.485delt p.(val162glyfs*50) minor Exon 4 c.496delg p.glu157fs Exon 4 c.519_520delinsga p.[cys173trp;his174asn] major Exon 5 c.557_562delinsatcggt p.[ala186asp;phe187arg] minor Exon 5 c.560_561insggt p.ser187_leu188insval Exon 5 c.570delg p.thr191fs major Exon 5 c.577delc p.leu193fs major Exon 5 c.577dupc p.leu193fs major <10% AGT activity in liver bx aa inserted incorrectly reported as gly. (Williams and Rumsby Hopp et al., 2015 Williams and Williams and Hopp et al., 2015 (Coulter- Mackie et al., 2004)

21 Exon 6 c.642_645deltcca p.pro215fs major Exon 6 c.661_663deltcc p.ser221del Exon6/Intron 6 c.679_680+2delaagt?missplicing or p.lys227glu major Exon 7 c _c del732instgaga NC_ :g _ del732insTGAGA p.lys228_met259del32 (in frame deletion of exon 7) Exon 7 c.725dupt p.asp243fs major Exon 7 c.744delc p.asp249fs major Exon 7 c.751_752delinsaa p.trp251lys (peroxisomal and cytosolic distribution) Exon 8 c.798_802delinsacaatctcag p.ile267fs major Exon 8 c.823_824dupag p.ser275fs unknown Exon8 c.829_830insa,c.830c>a p.ala277fs minor Exon 8 c.832delc p.leu278fs Exon 8 c.834delc p.ile279fs minor Exon 9 c _c del1121 NC_ :g _ del1122 deletion exon 9 Exon 9 c.860_861delinscg p.ser287thr unknown Exon 9 c.886_888delgcg Ala296del major Exon 9 c.919delc p.leu307fs major major (Coulter- Mackie, et al., 2001) (Robbiano et al., 2010) (Williams and (Coulter- Mackie et al., 2004) Kawai et al., 2012 (von Schnakenburg et al., 1998) (Yuen, et al., 2004) Williams and Hopp et al., 2015 (Coulter- Mackie et al., 2005) (Frishberg et al., 2005) (Von Schnakenburg and 1998)

22 Exon 10 c.959_960delca p.thr320fs Exon 10 c deltg p.val324fs major Exon 10 c.973delg p.ala325fs Exon 10 c.976delg p.val326fs major Exon 10 c.983_988delctggct p.ala328_tyr330delinsasp major Exon 11 c.1110_1111delcg p.asn372fs minor Exon 11 c.1125_1126delcg p.val376fs major Exon 11_3 UTRdel truncating Williams and Rumsby (Pirulli et al., 1999) (Coulter- Mackie et al., 2004) Williams and (Coulter- Mackie et al., 2001) (Monico et al., Ex1_5del Ex1_7del Ex5_11del g telomere 5-6 kb deletion 10 kb deletion >6kb deletion Major deletion including HDAC4 (Coulter- Mackie et al., 2001) (Nogueira et al., 2000) Tammachote et al., 2012

23 References Basmaison O, Rolland M-O, Cochat P, Bozon D Identification of 5 novel mutations in the AGXT gene. Hum Mutat.15:577 Coulter-Mackie MB, Applegarth D, Toone JR, Henderson H The major allele of the alanine:glyoxylate aminotransferase gene:seven novel mutations causing primary hyperoxaluria type 1. Mol Genet Metab 82: Coulter-Mackie MB, Lian Q Consequences of missense mutations for dimerisation and turnover of alanine:glyoxylate aminotransferase:study of a spectrum of mutations. Mol Genet Metab. Coulter-Mackie MB, Lian Q, Applegarth D, Toone JR The major allele of the alanine:glyoxylate aminotransferase gene:nine novel mutations and polymorphisms associated with primary hyperoxaluria type 1. Mol Genet Metab 86: Coulter-Mackie MB, Rumsby G, Applegarth DA, Toone JR Three novel deletions in the alanine:glyoxylate aminotransferase gene of three patients with type 1 hyperoxaluria. Mol Genet Metab 74: Coulter-Mackie MB, Tung A, Henderson HE, Toone JR, Applegarth DA The AGT gene in Africa: a distinct minor allele haplotype, a polymorphism (V326I) and a novel PH1 mutation (A112D) in black Africans. Mol Genet Metab 78: Danpure C, Jennings P, Freyer P, Purdue P, Allsop J. 1994a. Primary hyperoxaluria type 1: Genotypic and phenotypic heterogeneity. J Inherit Metab Dis 17: Danpure CJ, Birdsey GM, Rumsby G, Lumb MJ, Purdue PE, Allsop J. 1994b. Molecular characterization and clinical use of a polymorphic tandem repeat in an intron of the human alanine:glyoxylate aminotransferase gene. Hum Genet 94(1): Danpure CJ, Purdue PE, Fryer P, Griffiths S, Allsop J, Lumb MJ, Guttridge KM, Jennings PR, Scheinman JI, Mauer SM and others Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation. Am J Hum Genet 53(2):

24 Frishberg Y, Rinat C, Khatib I, Shalata A, Feinstein S, Becker-Cohen R, Weismann I, Wanders RJA, Rumsby G, Roels F and others Intra-familial clinical heterogeneity: Absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel. Am J Nephrol 25: Hopp K, Cogal A G, Bergstralh E J, Seide B M, Olson J B, Meek A M, Lieske J C, Milliner D S, Harris P C Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol 26: Feb 2. pii: JASN [Epub ahead of print] Hoyer-Kuhn H, Kohbrok S, Volland R, Franklin J, Hero B, Beck B B Vitamin B6 in primary hyperoxaluria type 1: First prospective trial after 40 years of practice. Clin J Am Soc Nephrol 9: Kawai C, Minatogawa Y, Akiyoshi H, Hirose, S, Suehiro T, Tone S A novel mutation of human liver alanine:glyoxylate aminotransferase causes primary hyperoxaluria type 1: immunohistochemical quantification and subcellular distribution. Acta Histochem.Cytochem 42: Laga M D, Pittman, A M C, Roncador A, Cellini A and Tucker C L Allele specific characterization of alanine:glyoxylate aminotransferase variants associated with primary hyperoxaluria. Plos One in press Lumb MJ, Danpure CJ Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease causing mutations. J Biol Chem 275: Minatogawa Y, Tone S, Allsop J, Purdue PE, Takada Y, Danpure CJ, Kido R A serine-to-phenylalanine substitution leads to loss of alanine:glyoxylate aminotransferase catalytic activity and immunoreactivity in a patient with primary hyperoxaluria type 1. Hum Mol Genet 1(8): Monico CG, Olson JB, Milliner DS Implications of genotype and enzyme phenotype in pyridoxine response of patients with type 1 primary hyperoxaluria. Am J Nephrol 25: Monico CG, Rossetti S, Schwanz HA, Olson JB, Lundquist PA, Dawson DB, Harris PC, Milliner DS Comprehensive mutation screening in 55 probands with type 1 primary hyperoxaluria type 1 primary hyperoxaluria shows feasibility of a gene-based diagnosis. J Am Soc Nephrol 18:

25 Nishiyama K, Funai T, Katafuchi R, Hattori F, Onoyama K, Ichiyama A Primary hyperoxaluria type I due to a point mutation of T to C in the coding region of the serine:pyruvate aminotransferase gene. Biochem Biophys Res Commun 176(3): Nogueira PK, Vuong TS, Boutoon O, Maillard A, Marchand M, Rolland MO, Cochat P, Bozon D Partial deletion of the AGXT gene (EX1_EX7del): A new genotype in hyperoxaluria type 1. Hum Mutat. 15: Oppici E, Roncador A, Montioli R, Bianconi S, Cellini B Gly161 mutations associated with primary hyperoxaluria type 1 induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase. Biochim Biophys Acta 1832: Pirulli D, Puzzer D, Ferri L, Crovella S, Amoroso A, Ferrettini C, Marangella M, Mazzola G, Florian F Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine:glyoxylate aminotransferase gene. Hum Genet 104(6): Pittmann A M C, Lage M D, Poltoratsky V, Vrana J D, Paiardini A, Roncador A, Cellini B, Hughes R M, Tucker C L Rapid profiling of disease alleles using a tunable reporter of protein misfolding. Genetics 192: Purdue P, Lumb M, Allsop J, Danpure C. 1991a. An intronic duplication in the alanine: glyoxylate aminotransferase gene facilitates identification of mutations in compound heterozygote patients with primary hyperoxaluria type 1. Hum Genet 87: Purdue P, Lumb M, Allsop J, Minatogawa Y, Danpure C A glycine-to-glutamate substitution abolishes alanine:glyoxylate aminotransferase catalytic activity in a subset of patients with primary hyperoxaluria type 1. Genomics 13: Purdue PE, Takada Y, Danpure CJ Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1. J Cell Biol 111: Rinat C, Wanders RJA, Drukker A, Halle D, Frishberg Y Primary hyperoxaluria type I: A model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol 10:

26 Robbiano A, Mandrile G, De Marchi M, Beck B, Baasner A, Murer L, Benetti E, Giachino D Novel human pathological mutations. Gene symbol:agxt.disease:hyperpoxaluria. Hum Genet 127(4):468 Tammachote R, Kingsuwannapong N, Tongkobpetch S, Srichomthong C, Yeetong P, Kingwatanakul P, Monico C G, Suphapeetiporn K, Shotelersuk V Primary hyperoxaluria type 1 and brachydactyly mental retardation caused by a novel mutation in AGXT and a terminal deletion of chromosome 2. Am J Med Genet 158A: Tintillier M, Pochet JM, Cosyns JP, Delgrange E, Donckier J Late onset primary hyperoxaluria triggered by hypothyroidism and presenting as rapidly progressive renal failure - description of a new mutation. Clin Nephrol 62: Van Woerden CS, Groothoff JW, Wijburg FA, Annink C, Wanders RJA, Waterham HR Clinical implications of mutation analysis in primary hyperoxaluria type 1. Kidney Int 66: Von Schnakenburg C Molecular analysis of the AGXT gene and linkage studies in primary hyperoxaluria type 1: PhD Thesis, University of London. von Schnakenburg C, Hulton SA, Milford DV, Roper HP, Rumsby G Variable presentation of primary hyperoxaluria type 1 in 2 patients homozygous for a novel combined deletion and insertion mutation in exon 8 of the AGXT gene. Nephron 78: von Schnakenburg C, Rumsby G Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene. J Med Genet 34(6): Von Schnakenburg C, Rumsby G Identification of new mutations in primary hyperoxaluria type 1 (PH1). J Nephrol 11(S1): Williams EL, Rumsby G Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of patients with primary hyperoxaluria type 1. Clin Chem 53: Williams E L, Acquaviva C, Amoroso A, Chevalier F, Coulter Mackie M, Monico C G, Giachino D, Owen E P, Robbiano A, Salido E, Waterham H, Rumsby G Primary hyperoxaluria type 1: Update and additional mutation analysis of the AGXT gene. Hum Mutat 30,1-8

27 Yuen Y, Lai C, Tong GM, Wong P, Wong FK, Mak S, Lo K, Wong AK, Tong S, Chan Y and others Novel mutations of the AGXT gene causing primary hyperoxaluria type 1. J Nephrol 17: