Submissions for variant NM_000277.3(PAH):c.1355dup (p.Ter453ValextTer?)

dbSNP: rs199475641

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169511	SCV000220980	likely pathogenic	Phenylketonuria	2014-12-22	criteria provided, single submitter	literature only
CeGaT Center for Human Genetics Tuebingen	RCV000088835	SCV001247316	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV000169511	SCV001400960	likely pathogenic	Phenylketonuria	2023-07-03	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 102596). This frameshift has been observed in individual(s) with mild phenylketonuria (PMID: 14722928). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the PAH gene (p.*453Valext*35). While this is not anticipated to result in nonsense mediated decay, it is expected to extend the length of the PAH protein by 35 additional amino acid residues.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169511	SCV003844606	likely pathogenic	Phenylketonuria	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1355dupA (p.X453ValfsX36) causes a frameshift which results in an extension of the protein. The variant was absent in 251194 control chromosomes (gnomAD). c.1355dupA has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (examples: AulehlaScholz_2003, Chien_2004, Sarkissian_2012, Reblova_2013). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088835	SCV000119427	not provided	not provided		no assertion provided	not provided