Submissions for variant NM_000277.3(PAH):c.740G>T (p.Gly247Val)

dbSNP: rs199475579

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169396	SCV000220792	likely pathogenic	Phenylketonuria	2014-10-14	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000089073	SCV000857831	pathogenic	not provided	2017-11-13	criteria provided, single submitter	clinical testing
Invitae	RCV000169396	SCV000946467	pathogenic	Phenylketonuria	2023-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 247 of the PAH protein (p.Gly247Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 26600521). 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: 102818). 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. Experimental studies have shown that this missense change affects PAH function (PMID: 17924342, 21953985). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169396	SCV001337905	pathogenic	Phenylketonuria	2020-01-10	criteria provided, single submitter	clinical testing	Variant summary: PAH c.740G>T (p.Gly247Val) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (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 251220 control chromosomes. c.740G>T has been frequently reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Li_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity reporting a functionally hemizygous genotype in combination with null mutations (Li_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000169396	SCV004209605	pathogenic	Phenylketonuria	2023-08-29	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089073	SCV000119679	not provided	not provided		no assertion provided	not provided