Submissions for variant NM_000277.3(PAH):c.824C>G (p.Pro275Arg)

dbSNP: rs62508715

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000672381	SCV000886555	likely pathogenic	Phenylketonuria	2018-12-09	reviewed by expert panel	curation	The c.824C>G (p.Pro275Arg) variant in PAH is absent from population databases and predicted deleterious by multiple in silico algorithms. It is in the same codon as two previously reported likely pathogenic variants (p.Pro275Ser and p.Pro275Leu). It has been identified in trans with a pathogenic variant (PMID: 23514811), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in that patient. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PM5, PP3.
Counsyl	RCV000672381	SCV000797480	likely pathogenic	Phenylketonuria	2018-01-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672381	SCV000932925	pathogenic	Phenylketonuria	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 275 of the PAH protein (p.Pro275Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 15464430, 25882749, 27121329). ClinVar contains an entry for this variant (Variation ID: 102854). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672381	SCV004030147	pathogenic	Phenylketonuria	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: PAH c.824C>G (p.Pro275Arg) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251346 control chromosomes (gnomAD). c.824C>G has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (examples: Aldamiz-Echevarria_2016). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27121329). Other variants affecting the same codon have been classified pathogenic in ClinVar (CV IDs: 102855, 102853). Three submitters (including ClinGen PAH Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000672381	SCV005053805	pathogenic	Phenylketonuria	2024-03-30	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089115	SCV000119722	not provided	not provided		no assertion provided	not provided