Submissions for variant NM_000277.3(PAH):c.211C>T (p.Arg71Cys)

gnomAD frequency: 0.00001  dbSNP: rs866012140

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003058394	SCV003441292	likely pathogenic	Phenylketonuria	2023-12-27	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 71 of the PAH protein (p.Arg71Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 17627389). ClinVar contains an entry for this variant (Variation ID: 2137414). 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.Arg71 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10495930, 29390883). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003058394	SCV004241037	likely pathogenic	Phenylketonuria	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: PAH c.211C>T (p.Arg71Cys) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes (gnomAD). c.211C>T has been reported in the literature in an individual affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example: Wang_2007). Different variants affecting the same residue (p.Arg71His, p.Arg71Pro) have been classified pathogenic/likely pathogenic in ClinVar. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 17627389).One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.