Submissions for variant NM_000277.3(PAH):c.1030G>A (p.Gly344Ser)

dbSNP: rs62508679

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001379649	SCV001762321	likely pathogenic	Phenylketonuria	2021-06-11	reviewed by expert panel	curation	The c.1030G>A (p.Gly344Ser) variant in PAH has been reported in multiple individuals with PKU and mild PKU (BH4 deficiency excluded). (PMID: 26503515, 29390883, 9634518). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.Q419R (PMID: 26600521). Other missense changes at the same amino acid residue have been seen before (p.Gly344Asp, p.Gly344Arg, p.Gly344Val are Likely pathogenic by PAH VCEP). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379649	SCV001577486	likely pathogenic	Phenylketonuria	2020-04-07	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Gly344 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 10679941, 18985011), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has been observed in individual(s) with phenylketonuria (PMID: 26600521, 17502162). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102479). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 344 of the PAH protein (p.Gly344Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088710	SCV000119290	not provided	not provided		no assertion provided	not provided