Submissions for variant NM_000277.3(PAH):c.344_347del (p.Lys115fs)

dbSNP: rs199475648

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001175457	SCV002818520	pathogenic	Phenylketonuria	2022-10-14	reviewed by expert panel	curation	This c.344_347del (p.Lys115fs) variant in PAH was detected with the c.1315+1G>A pathogenic variant and the c.1066-14C>G likely pathogenic variant in multiple patients with PKU, phasing was not available (PMID: 11207989, 28676969, 25551302). This variant was absent in population databases. This is a frameshift variant in exon 3 of 13 coding exons with termination at position 194 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, PM2, PM3_Supporting, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175457	SCV001339027	pathogenic	Phenylketonuria	2020-03-01	criteria provided, single submitter	clinical testing	Variant summary: PAH c.344_347delAAGA (p.Lys115ThrfsX79) 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 251430 control chromosomes. c.344_347delAAGA has been reported in the literature in individuals from diverse ethnicities affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Kimura_2001, Razipour_2017) and has been subsequently cited by others. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088899	SCV000119497	not provided	not provided		no assertion provided	not provided