Submissions for variant NM_000277.3(PAH):c.580_581del (p.Leu194fs)

dbSNP: rs62508587

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169180	SCV001448677	pathogenic	Phenylketonuria	2020-10-30	reviewed by expert panel	curation	The c.578_579del PAH variant has been identified in at least one patient with classic PKU (PMID: 26666653). The patient was compound heterozygous with the pathogenic variant Leu348Val (ClinVar 92727). This variant is absent from 1000G, ESP, and gnomAD databases. This variant leads to the frameshift Leu194GlufsTer5, creating a stop codon in exon 6 of 13 which is predicted to cause NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2, PM3_supporting.
Counsyl	RCV000169180	SCV000220417	likely pathogenic	Phenylketonuria	2014-06-16	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169180	SCV002511464	pathogenic	Phenylketonuria	2022-04-22	criteria provided, single submitter	clinical testing	Variant summary: PAH c.580_581delCT (p.Leu194GlufsX5) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251338 control chromosomes (gnomAD). c.580_581delCT has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, e.g. Aulehla-Scholz_2003, Sarkissian_2012, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (an expert panel) has assessed this variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000169180	SCV005053834	pathogenic	Phenylketonuria	2024-01-24	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088990	SCV000119594	not provided	not provided		no assertion provided	not provided