ClinVar Miner

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

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Total submissions: 6
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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.
Counsyl RCV000281383 SCV000800539 uncertain significance Phenylketonuria 2017-05-22 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089101 SCV000119708 not provided not provided no assertion provided not provided
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089101 SCV000330984 pathogenic not provided 2015-06-12 criteria provided, single submitter clinical testing
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.
Invitae RCV000281383 SCV000827700 pathogenic Phenylketonuria 2018-11-09 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.

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