ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.559T>C (p.Trp187Arg) (rs62507272)

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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 RCV000671079 SCV001146738 likely pathogenic Phenylketonuria 2018-12-11 reviewed by expert panel curation The PAH: c.559T>C (p.Trp187Arg) variant was found in two cases in trans with other P/LP alleles: one case with classic PKU (assessed via plasma Phe measurement in trans with the p.R158Q allele (PMID: 18956252) and one case whose PKU sub-phenotype was not mentioned in trans with the p.R261Q allele (PMID: 23074961) (PM3_Strong). It has also been found in trans with the p.Gln419Arg allele, classified as Likely Pathogenic in ClinVar, in 1 case with mild hyperphenylalanemia (BH4 deficiency excluded. PP4_moderate. PMID: 28982351). The variant is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is predicted damaging by multiple lines of computational evidence: SIFT, Polyphen2, Mutation Taster, REVEL = 0.918 (PP3). 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, PP3.
GeneDx RCV000088984 SCV000583340 likely pathogenic not provided 2017-02-28 criteria provided, single submitter clinical testing The W187R variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The W187R variant has been reported ina patient with PKU who also harbored a second missense change in the PAH gene and who wasreported to be responsive to BH4 therapy (Trefz et al. 2009). The W187R variant is not observed inlarge population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome VariantServer). The W187R variant is a non-conservative amino acid substitution, which is likely to impactsecondary protein structure as these residues differ in polarity, charge, size and/or other properties.This substitution occurs at a position that is conserved across species, and in silico analysis predictsthis variant is probably damaging to the protein structure/function. In summary, we interpret theW187R variant as likely pathogenic
Counsyl RCV000671079 SCV000796021 uncertain significance Phenylketonuria 2017-11-30 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088984 SCV000119588 not provided not provided no assertion provided not provided

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