Submissions for variant NM_000277.3(PAH):c.1237C>A (p.Arg413Ser)

dbSNP: rs62644467

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001380994	SCV005442789	pathogenic	Phenylketonuria	2024-09-06	reviewed by expert panel	curation	The c.1237C>A (p.Arg413Ser) variant in PAH has been reported in 1 patient with mild hyperphenylalenemia (BH4 deficiency excluded). This variant has been reported in at least 2 in vitro studies showing <50% PAH activity as compared to wild type. This variant is absent from population databases, and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, REVEL = 0.934. This variant is at the same codon as c.1238G>C (p.Arg413Pro) which has been curated as pathogenic by the ClinGen PAH VCEP (ClinVarID:592). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM5, PP4_Moderate, PP3_strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380994	SCV001579239	pathogenic	Phenylketonuria	2020-03-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with serine at codon 413 of the PAH protein (p.Arg413Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another PAH variant in an individual affected with hyperphenylaninemia (PMID: 10479481). ClinVar contains an entry for this variant (Variation ID: 102575). This variant has been reported to affect PAH protein function (PMID: 10479481). This variant disrupts the p.Arg413 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24401910, 27264808, 17935162, 21953985, 30459323). 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.
Baylor Genetics	RCV001380994	SCV005053829	likely pathogenic	Phenylketonuria	2024-02-08	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088811	SCV000119401	not provided	not provided		no assertion provided	not provided