ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.826A>G (p.Met276Val) (rs62516149)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000664652 SCV000886624 likely pathogenic Phenylketonuria 2018-12-09 reviewed by expert panel curation The c.826A>G (p.Met276Val) variant in PAH is absent from population databases. It has been identified in trans with pathogenic variants in two patients (A300S and R261Q; PMID: 16198137), and identified in an additional patient in which a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID: 9634518). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.
Counsyl RCV000664652 SCV000788652 likely pathogenic Phenylketonuria 2017-10-04 criteria provided, single submitter clinical testing
Invitae RCV000664652 SCV001386781 pathogenic Phenylketonuria 2019-04-03 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 276 of the PAH protein (p.Met276Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another PAH variant in individuals affected with hyperphenylalaninemia (PMID: 16198137, 16290003, Invitae). ClinVar contains an entry for this variant (Variation ID: 102856). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). For these reasons, this allele has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089117 SCV000119724 not provided not provided no assertion provided not provided

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