Submissions for variant NM_000277.3(PAH):c.157C>T (p.Arg53Cys)

gnomAD frequency: 0.00003  dbSNP: rs199475619

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000664566	SCV001762319	likely pathogenic	Phenylketonuria	2021-05-29	reviewed by expert panel	curation	This c.157C>T (p.Arg53Cys) variant in PAH was reported in trans with pathogenic variant p.Arg158Gln in 1 patient with PAH deficiency (324 uMol/L Phe) (PMID: 28982351). This variant was found at an amino acid residue where p.Arg53His, a missense variant of uncertain significance, has been seen before. Computational evidence for this missense variant supports a deleterious effect (REVEL=0.766). This variant is found at an extremely low frequency in gnomAD and ExAC (MAF=0.00012), and absent from 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4.
Counsyl	RCV000664566	SCV000788553	uncertain significance	Phenylketonuria	2017-12-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000664566	SCV002317207	pathogenic	Phenylketonuria	2024-10-23	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 53 of the PAH protein (p.Arg53Cys). This variant is present in population databases (rs199475619, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 28982351; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102600). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281929	SCV002571984	uncertain significance	not specified	2022-08-12	criteria provided, single submitter	clinical testing	Variant summary: PAH c.157C>T (p.Arg53Cys) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251390 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.157C>T has been reported in the literature in at least one individual affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, Liu_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters, including one expert panel, have assessed the variant since 2014: one classified the variant as of uncertain significance, and two (including the expert panel) classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000664566	SCV003816614	likely pathogenic	Phenylketonuria	2023-06-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000088841	SCV005326122	likely pathogenic	not provided	2023-10-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a child with mild hyperphenylalaninemia (Liu et al., 2017); This variant is associated with the following publications: (PMID: 29316886, 28982351, 17924342)
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088841	SCV000119434	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004739363	SCV005351617	likely pathogenic	PAH-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The PAH c.157C>T variant is predicted to result in the amino acid substitution p.Arg53Cys. This variant has been reported in the compound heterozygous state in an individual(s) with PAH deficiency (PubMed ID: Liu N et al. 2017. PubMed ID: 28982351). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic by the ClinGen PAH Variant Curation Expert Panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/102600/). Taken together, we classify this variant as likely pathogenic.