Submissions for variant NM_000277.3(PAH):c.770G>T (p.Gly257Val)

dbSNP: rs62642908

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000668413	SCV002540127	pathogenic	Phenylketonuria	2020-11-14	reviewed by expert panel	curation	The c.770G>T (p.Gly257Val) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) (PMID: 26503515). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.R408Q, p.Ser70del (PMID: 26322415); p.R111X (PMID: 14722928); p.Arg261Gln (PMID: 17502162); c.1068C>A (p.Y356*, PMID: 25894915); p.Arg252Trp, p.Arg243Gln, p.His107Arg, p.Leu255Ser (PMID: 28982351). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3.
Counsyl	RCV000668413	SCV000793007	likely pathogenic	Phenylketonuria	2017-07-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668413	SCV000919916	pathogenic	Phenylketonuria	2018-08-02	criteria provided, single submitter	clinical testing	Variant summary: PAH c.770G>T (p.Gly257Val) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (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 246102 control chromosomes (in gnomAD). c.770G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Liang 2014, Li 2015, Liu 2017). 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 (Liang 2014). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089087	SCV000119693	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000668413	SCV002088646	pathogenic	Phenylketonuria	2021-07-08	no assertion criteria provided	clinical testing