Submissions for variant NM_000277.3(PAH):c.176A>T (p.Asp59Val)

gnomAD frequency: 0.00001  dbSNP: rs199475672

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000758107	SCV000886580	uncertain significance	Phenylketonuria	2018-12-10	reviewed by expert panel	curation	The c.176A>T (p.Asp59Val) variant in PAH has been reported in an Italian patient with mild PKU (BH4 deficiency not totally excluded) with pathogenic variant p.R261Q (PP4, PM3; PMID: 25003100) This variant is absent from 1000G, ESP, ExAC and gnomAD. computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758107	SCV002951270	pathogenic	Phenylketonuria	2022-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 59 of the PAH protein (p.Asp59Val). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp59 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 10234516, 12655546, 30037505), which suggests that this may be a clinically significant amino acid residue. 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: 619154). This missense change has been observed in individual(s) with phenylketonuria (PMID: 25003100, 31623983). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235382	SCV003934426	uncertain significance	not specified	2023-05-12	criteria provided, single submitter	clinical testing	Variant summary: PAH c.176A>T (p.Asp59Val) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250790 control chromosomes. c.176A>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Rajabi_2019, Leuzzi_2014). Two other variants altering the same amino acid (p.D59Y, p.D59G) have been observed in association with PKU. The available evidence at this time is insufficient at this time to suggest a definitive role for this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25003100, 31623983). One clinical diagnostic laboratory and a ClinGen expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014. Clinical laboratory classified the variant as pathogenic, and the expert panel classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.