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

gnomAD frequency: 0.00001  dbSNP: rs62507272

Total submissions: 4

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