ClinVar Miner

Submissions for variant NM_000277.1(PAH):c.664_665delGA (p.Asp222Terfs) (rs62514936)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169088 SCV000220265 likely pathogenic Phenylketonuria 2014-04-23 criteria provided, single submitter literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089025 SCV000119630 not provided not provided no assertion provided not provided
Integrated Genetics/Laboratory Corporation of America RCV000169088 SCV000917933 pathogenic Phenylketonuria 2018-12-20 criteria provided, single submitter clinical testing Variant summary: PAH c.664_665delGA (p.Asp222X) 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 1.8e-05 in 277080 control chromosomes (gnomAD). c.664_665delGA has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) with limited residual activity <10% (Bayat_2016, Zurfluh_2008). These data indicate that the variant is very likely to be associated with disease. 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.
Invitae RCV000169088 SCV000937953 pathogenic Phenylketonuria 2018-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp222*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs759154440, ExAC 0.001%). This variant has been observed to be homozygous or in combination with another PAH variant in individuals affected with phenylketonuria (PMID: 24350308, 18937047, 26666653). ClinVar contains an entry for this variant (Variation ID: 188766). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.

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