ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.830A>G (p.Tyr277Cys)

gnomAD frequency: 0.00001  dbSNP: rs62516155
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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 RCV000411640 SCV002032222 pathogenic Phenylketonuria 2020-06-08 reviewed by expert panel curation The c.830A>G (p.Tyr277Cys) variant in PAH has been reported in multiple individuals with PKU (PMID:24350308). This variant has an extremely low allele frequency (MAF=0.00006) in gnomAD. It was detected with multiple pathogenic variants: p.R408W in 2 patients; p.L194P (PMID: 24350308); c.842+1G>A in 2 patients (PMID: 25952249). Computational prediction tools and conservation analysis support a deleterious effect. Another missense change at the same amino acid (p.Y277D), is pathogenic by 8 submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP3, PP4
Counsyl RCV000411640 SCV000486807 likely pathogenic Phenylketonuria 2016-08-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000411640 SCV003441218 pathogenic Phenylketonuria 2022-08-31 criteria provided, single submitter clinical testing This variant disrupts the p.Tyr277 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2035532, 8268925, 8632937, 12173030, 12655546). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 277 of the PAH protein (p.Tyr277Cys). This variant is present in population databases (rs62516155, gnomAD 0.006%). This missense change has been observed in individuals with phenylketonuria (PMID: 32668217). ClinVar contains an entry for this variant (Variation ID: 102860).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089121 SCV000119729 not provided not provided no assertion provided not provided

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