Submissions for variant NM_000277.3(PAH):c.231T>G (p.Tyr77Ter)

dbSNP: rs62507332

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV003479001	SCV004222621	pathogenic	Phenylketonuria	2023-10-15	reviewed by expert panel	curation	The NM_000277.3(PAH):c.231T>G (p.Tyr77Ter) is a nonsense variant in exon 3/13 of PAH, and is predicted to result in PTC with removal of >10% of the protein and NMD (PVS1). The variant is absent from population databases including gnomAD, ExAC, and ESP, and is present at an extremely low allele frequency (MAF < 0.0002) in the 1000 Genomes (PM2_supporting). The variant has been previously reported in a patient with PKU (plasma Phe level not specified) and BH4 deficiency excluded (PMID: 9860305; PMID: 21307867) (PP4_Moderate); the patient’s genotype was not specified. It has also been noted (PMID: 28982351) in a patient with mild PKU (plasma Phe 720 uM) and BH4 deficiency excluded (PP4_Moderate), who harbored it in trans with the p.Asp101Asn (Likely Pathogenic in ClinVar, ID 553851) and p.Gly247Arg (Likely Pathogenic in ClinVar, ID 102816) alleles (PM3). In summary, this variant meets criteria to be classified as for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PM3, PP4_Moderate.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088879	SCV000119476	not provided	not provided		no assertion provided	not provided