Submissions for variant NM_000277.3(PAH):c.1237C>T (p.Arg413Cys)

gnomAD frequency: 0.00004  dbSNP: rs62644467

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001269321	SCV001448672	uncertain significance	Phenylketonuria	2020-05-14	reviewed by expert panel	curation	The variant c.1237C>T (p.Arg313Cys) in PAH is not currently reported in patients in the literature. This variant is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.937 (PP3), and has an extremely low frequency in gnomAD (PM2). 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) (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001269321	SCV002262977	likely pathogenic	Phenylketonuria	2024-03-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 413 of the PAH protein (p.Arg413Cys). This variant is present in population databases (rs62644467, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 32668217; Invitae). ClinVar contains an entry for this variant (Variation ID: 102576). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. 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: 17935162, 21953985, 24401910, 27264808). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415874	SCV004116738	uncertain significance	PAH-related disorder	2023-03-20	criteria provided, single submitter	clinical testing	The PAH c.1237C>T variant is predicted to result in the amino acid substitution p.Arg413Cys. This variant has been reported in association with phenylketonuria (PKU) and hyperphenylalaninemia (HPA) (Zurflüh et al. 2008. PubMed ID: 17935162; Table S2, Hillert et al. 2020. PubMed ID: 32668217). Another variant impacting this same amino acid has been reported in association with classical PKU and hyperphenylalaninemia (HPA) [c.1238C>G (p.Arg413Pro); Zurflüh et al. 2008. PubMed ID: 17935162; Liang et al. 2014. PubMed ID: 24401910] and computation studies analyzing protein function determine that variant likely impacts protein function (Zurflüh et al. 2008. PubMed ID: 17935162; Shi et al. 2011. PubMed ID: 21953985). The c.1237C>T (p.Arg413Cys) variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-103234256-G-A) and is interpreted as uncertain in ClinVar by a ClinGen expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/102576/). While this variant may be causative, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV001269321	SCV005053819	likely pathogenic	Phenylketonuria	2024-03-03	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088812	SCV000119402	not provided	not provided		no assertion provided	not provided