ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1579del (p.Thr526_Leu527insTer) (rs794729126)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183789 SCV000236270 pathogenic not provided 2015-11-02 criteria provided, single submitter clinical testing Although the c.1579delC mutation in the PKP2 gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Leucine 527, which creates a stop codon at this position, denoted p.Leu527Stop. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other loss-of-function mutations in the PKP2 gene have been reported in association with ARVC. In summary, c.1579delC mutation in the PKP2 gene is interpreted as a disease-causing mutation.
Integrated Genetics/Laboratory Corporation of America RCV001251408 SCV001426997 pathogenic Arrhythmogenic right ventricular dysplasia/cardiomyopathy 2020-07-27 criteria provided, single submitter clinical testing Variant summary: PKP2 c.1579delC (p.Leu527X) 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 in PKP2 associated Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVC). Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251366 control chromosomes. c.1579delC has been reported in the literature in at-least one individual affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in a WES study evaluating the prevalence, penetrance and associated phenotype of ARVC in a general clinical population cohort (Carruth_2019, 61 019 individuals in the DiscovEHR cohort). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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