Submissions for variant NM_000277.3(PAH):c.1099del (p.Leu367fs)

dbSNP: rs62506951

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000781680	SCV002818507	pathogenic	Phenylketonuria	2022-07-30	reviewed by expert panel	curation	The frameshift variant c.1099del (HGVS nomenclature c.1095del) occurs in exon 11 of 13 and is predicted to result in NMD. The variant is found at an extremely low allele frequency of 0.000003980 overall in gnomAD with a MAF of 0.000008804 (1/113590) in the European population. One classical PKU patient has been reported (PMID: 29176022) with this variant in trans with Arg241Cys (ClinVar 102803, Pathogenic with expert panel review). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4_moderate.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781680	SCV000919922	likely pathogenic	Phenylketonuria	2018-08-27	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1099delC (p.Leu367TrpfsX33) 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 allele was found at a frequency of 4.1e-06 in 245994 control chromosomes. c.1099delC has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant may 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781680	SCV001199465	pathogenic	Phenylketonuria	2021-03-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu367Trpfs*33) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 29176022, 29499199). ClinVar contains an entry for this variant (Variation ID: 102524). For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088757	SCV000119341	not provided	not provided		no assertion provided	not provided