Submissions for variant NM_000277.3(PAH):c.782G>C (p.Arg261Pro)

dbSNP: rs5030849

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000410877	SCV001146697	pathogenic	Phenylketonuria	2019-08-11	reviewed by expert panel	curation	The PAH c.782G>C (p.Arg261Pro) variant has been reported in multiple affected individuals (PMID: 26666653, Bh4 deficiency not ruled out, PP4). It has been detected with 5 known pathogenic variants (PM3_S). It is absent from ExAC/gnomAD. Computational evidence supports a deleterious effect. Also, p.R261Q is interpreted as pathogenic. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_S, PM2, PM5, PP4, PP3.
Counsyl	RCV000410877	SCV000485544	likely pathogenic	Phenylketonuria	2016-01-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410877	SCV003441285	pathogenic	Phenylketonuria	2022-06-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg261 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2574153, 16765994). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PAH function (PMID: 27620137). 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. ClinVar contains an entry for this variant (Variation ID: 102832). This missense change has been observed in individuals with phenylketonuria (PMID: 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 261 of the PAH protein (p.Arg261Pro).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410877	SCV005202719	pathogenic	Phenylketonuria	2024-07-10	criteria provided, single submitter	clinical testing	Variant summary: PAH c.782G>C (p.Arg261Pro) 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 251358 control chromosomes. c.782G>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), including as a compound heterozygous phenotype (e.g. Jeannesson-Thivisol_2015). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.782G>A, p.Arg261Gln), supporting the critical relevance of codon 261 to PAH protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in ~10% of normal enzyme activity in vitro (e.g. Trunzo_2016). The following publications have been ascertained in the context of this evaluation (PMID: 26666653, 27620137). ClinVar contains an entry for this variant (Variation ID: 102832). Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089091	SCV000119698	not provided	not provided		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000089091	SCV001927087	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000089091	SCV001957349	pathogenic	not provided		no assertion criteria provided	clinical testing