Submissions for variant NM_000277.3(PAH):c.514C>T (p.Gln172Ter)

dbSNP: rs199475588

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001238801	SCV002818517	pathogenic	Phenylketonuria	2022-10-14	reviewed by expert panel	curation	This c.514C>T (p.Gln172Ter) variant in PAH was detected in multiple patients with PKU with pathogenic variants c.1315+1G>A (PMID:8889590) and p.Ala345Thr (PMID:28754886). This variant was absent in population databases. This was predicted as a null variant in PAH where LOF is a known mechanism of disease. This is a nonsense variant in exon 6 of 13 coding exons predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, PP4_moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001238801	SCV001411630	pathogenic	Phenylketonuria	2019-10-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln172*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with phenylketonuria (PMID: 8889590, 19915519). ClinVar contains an entry for this variant (Variation ID: 102718). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001238801	SCV002511462	pathogenic	Phenylketonuria	2022-04-09	criteria provided, single submitter	clinical testing	Variant summary: PAH c.514C>T (p.Gln172X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250994 control chromosomes. c.514C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Guldberg_1996, Zhu_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088966	SCV000119569	not provided	not provided		no assertion provided	not provided