ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.14del (p.Gly5fs) (rs397516996)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038166 SCV000061832 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2012-11-20 criteria provided, single submitter clinical testing The Gly5Alafs variant in PKP2 has not been reported in the literature nor previo usly identified by our laboratory. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 5 and lead to a prematu re termination codon 34 amino acids downstream. This alteration is then predicte d to lead to a truncated or absent protein. Heterozygous loss-of-function varian ts in the PKP2 gene are common in patients with ARVC. In summary, this variant i s likely to be pathogenic, though additional studies are required to fully estab lish its clinical significance.
GeneDx RCV000183791 SCV000236272 pathogenic not provided 2017-08-17 criteria provided, single submitter clinical testing Although the c.14delG mutation in the PKP2 gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Glycine 5, changing it to an Alanine, and creating a premature stop codon at position 34 of the new reading frame, denoted p.Gly5AlafsX34. 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 frameshift mutations in the PKP2 gene have been reported in association with ARVC.
RBHT Clinical Genetics and Genomics Laboratory,Royal Brompton and Harefield NHS Foundation Trust RCV000714902 SCV000845655 pathogenic Arrhythmogenic ventricular cardiomyopathy 2017-09-12 criteria provided, single submitter clinical testing This variant causes a frameshift, and is predicted to lead to the introduction of a premature termination codon, generating a truncated or absent protein. Loss of function variants in PKP2 are known to be pathogenic. This variant has not been detected in approximately 60,000 individuals in control populations (ExAC database), and has been reported in other individuals with ARVC (ClinVar variation ID 45027; Groeneweg et al. Circ Cardiovasc Genet. 2015;8:437-46). It has been shown to segregate with disease in mutiple family members in our lab.
Integrated Genetics/Laboratory Corporation of America RCV000780605 SCV000918020 pathogenic Cardiac arrhythmia 2018-10-05 criteria provided, single submitter clinical testing Variant summary: PKP2 c.14delG (p.Gly5AlafsX34) 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 (e.g., p.Arg79X and p.Gln133X). The variant was absent in 30714 control chromosomes. c.14delG has been reported in the literature in one individual affected with Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). 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. Another clinical diagnostic laboratory has submitted assessment for this variant to ClinVar before 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Therefore, at-least 3 index cases with this variant have been identified. Based on the evidence outlined above, the variant was classified as Pathogenic.

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