ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.805A>C (p.Ile269Leu) (rs62508692)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000281383 SCV000886598 pathogenic Phenylketonuria 2018-12-10 reviewed by expert panel curation The c.805A>C (p.Ile269Leu) variant in PAH has been reported in multiple individuals with PAH deficiency, including non-PKU HPA (BH4 deficiency excluded). (PP4_Moderate; PMID10767174, PMID 2350059). This variant has an extremely low allele frequency in ExAC and gnomAD (PM2; ENF=0.00013). This variant was detected in trans with multiple known pathogenic variants: PMID 9521426: c.842+3G>C; PMID 10767174: R261X; PMID 14726806: E280K; PMID 21871829: IVS10-11G>A (PM3_Very-strong). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Very-strong, PP4_Moderate, PM2, PP3.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000089101 SCV000330984 pathogenic not provided 2015-06-12 criteria provided, single submitter clinical testing
Invitae RCV000281383 SCV000827700 pathogenic Phenylketonuria 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 269 of the PAH protein (p.Ile269Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs62508692, ExAC 0.03%). This variant has been reported as in combination with another PAH variant in individuals affected with hyperphenylalaninemia (PMID: 9521426, 23500595, 14726806, 21871829). ClinVar contains an entry for this variant (Variation ID: 102842). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000281383 SCV000915570 likely pathogenic Phenylketonuria 2018-11-02 criteria provided, single submitter clinical testing The PAH c.805A>C (p.Ile269Leu) variant has been reported in three studies in which it is found in a total of five individuals, including one sibling pair, with non-phenylketonuria hyperphenylalaninemia (non-PKU HPA). The variant was found in four individuals in a compound heterozygous state and in one individual in cis with a second missense variant and in trans with a third missense variant (Bosco et al. 1998; Rivera et al. 2011; Reblova et al. 2013). Control data are unavailable for the p.Ile269Leu variant which is reported at a frequency of 0.000464 in the Other population of the Genome Aggregation Database. Leandro et al. (2001) showed that the p.Ile269Leu variant caused a moderate reduction in the specific activity of the PAH enzyme as compared to wild type, when expressed in a prokaryotic expression system. Based on the evidence, the p.Ile269Leu variant is classified as likely pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000281383 SCV001362291 pathogenic Phenylketonuria 2020-07-20 criteria provided, single submitter clinical testing Variant summary: PAH c.805A>C (p.Ile269Leu) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251364 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (9.2e-05 vs 0.0079), allowing no conclusion about variant significance. c.805A>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency, including non-PKU hyperphenylalaninemia (e.g. Matalon_2004, Rivera_2011, Couce_2013, Reblova_2013). These data indicate that the variant is very likely to be associated with disease. In vitro studies demonstrated a moderate reduction in residual PAH activity (63%) as compared to wild type (Rivera_2011). Four ClinVar submitters including an expert panel (ClinGen PAH Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic while, one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000089101 SCV001784251 pathogenic not provided 2021-05-05 criteria provided, single submitter clinical testing Classified as responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 32668217, 9521426, 27121329, 17935162, 14726806, 11708866, 23357515, 23500595, 21871829, 17924342, 17513426, 10767174)
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089101 SCV000119708 not provided not provided no assertion provided not provided
Counsyl RCV000281383 SCV000800539 uncertain significance Phenylketonuria 2019-01-16 no assertion criteria provided clinical testing
Elsea Laboratory,Baylor College of Medicine RCV000281383 SCV001424211 likely pathogenic Phenylketonuria 2020-04-01 no assertion criteria provided clinical testing
Natera, Inc. RCV000281383 SCV001453104 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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