Submissions for variant NM_000277.3(PAH):c.665A>G (p.Asp222Gly)

gnomAD frequency: 0.00001  dbSNP: rs62507319

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001381395	SCV002032209	likely pathogenic	Phenylketonuria	2020-07-09	reviewed by expert panel	curation	The c.665A>G (p.Asp222Gly) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 24510552, 9429153); One had BH4 cofactor deficiency excluded (PMID: 15589814). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.A104D (PMID: 9429153); p.R408W (PMID: 15589814); c.1066-11G>A (PMID: 23842451); p.L48S (PMID: 25757997); p.I65T (PMID: 16165389). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.
Invitae	RCV001381395	SCV001579773	pathogenic	Phenylketonuria	2023-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 102775). This missense change has been observed in individual(s) with phenylketonuria (PMID: 9429153, 10598814, 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 222 of the PAH protein (p.Asp222Gly).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001381395	SCV002511463	pathogenic	Phenylketonuria	2022-04-26	criteria provided, single submitter	clinical testing	Variant summary: PAH c.665A>G (p.Asp222Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251340 control chromosomes. c.665A>G has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001381395	SCV003810754	likely pathogenic	Phenylketonuria	2021-11-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001381395	SCV004209708	pathogenic	Phenylketonuria	2023-01-23	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089026	SCV000119631	not provided	not provided		no assertion provided	not provided