Submissions for variant NM_000277.3(PAH):c.1076C>G (p.Ser359Ter)

dbSNP: rs5030854

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000658	SCV001370837	pathogenic	Phenylketonuria	2020-06-26	reviewed by expert panel	curation	The c.1076C>G (p.Ser359Ter) variant in PAH has been reported in an individual with PKU; BH4 deficiency excluded (PP4_Moderate; PMID: 8097261; (PMID: 9634518). This variant is absent in population databases (PM2). It is a nonsense variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000658	SCV004294268	pathogenic	Phenylketonuria	2023-01-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Ser359*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 8097261, 32668217). ClinVar contains an entry for this variant (Variation ID: 626).
OMIM	RCV000000658	SCV000020808	pathogenic	Phenylketonuria	1993-03-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088747	SCV000119331	not provided	not provided		no assertion provided	not provided