ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.529G>A (p.Val177Met) (rs199475602)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000534379 SCV000886567 pathogenic Phenylketonuria 2018-12-10 reviewed by expert panel curation The c.529G>A (p.Val177Met) variant in PAH was detected in a patient with Mild hyperphenylalaninemia (BH4 deficiency ruled out). PMID: 12501224 It has been detected with known pathogenic variants R408W (PMID: 12501224), and IVS12+1G>A (PMID: 23764561). It is absent from 1000G, ESP, and gnomAD; and at extremely low frequency in ExAC (MAF=0.00003). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.89. A different pathogenic missense change has been seen at this amino acid (V177L). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3.
Invitae RCV000534379 SCV000629200 pathogenic Phenylketonuria 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 177 of the PAH protein (p.Val177Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs199475602, ExAC 0.003%). This variant has been reported in the literature in multiple individuals affected with mild hyperphenylalaninemia (HPA) in the compound heterozygous state (PMID: 23500595, 12501224, 27121329, 23430547, 23764561, 17096675). ClinVar contains an entry for this variant (Variation ID: 102726). 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"). A different missense substitution at this codon (p.Val177Leu) has been determined to be pathogenic (PMID: 8659548, 22526846, 21445337). This suggests that the valine residue is critical for PAH protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000589313 SCV000696455 pathogenic Hyperphenylalaninemia, non-pku 2016-08-04 criteria provided, single submitter clinical testing Variant summary: The PAH c.529G>A (p.Val177Met) variant is located in the catalytic domain and causes a missense change involving a conserved nucleotide with 4/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/120722 (1/60361), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest has been reported in multiple affected individuals as a compound heterozygote, predominanlty in patients with mild hyperphenylalaninemia. A database cites the variant, however, with no classification being provided. Furthermore, another variant at this position, V177L (c.529G>C), has been reported as a pathogenic variant, as well. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088975 SCV000119578 not provided not provided no assertion provided not provided
Counsyl RCV000534379 SCV000795816 likely pathogenic Phenylketonuria 2017-11-17 no assertion criteria provided clinical testing

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