ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.837_838del (p.Val280fs) (rs772220644)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505802 SCV000236266 likely pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing Although the c.837_838delCG likely pathogenic variant in the PKP2 gene has not been reported to our knowledge, it has been identified in other unrelated individuals tested for cardiomyopathy at GeneDx. This variant causes a shift in reading frame starting at codon Valine 280, changing it to a Histidine, and creating a premature stop codon at position 55 of the new reading frame, denoted p.Val280HisfsX55. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other downstream frameshift variants in the PKP2 gene have been reported in HGMD in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Stenson et al., 2014). Furthermore, the c.837_838delCG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.While the c.837_838delCG variant has not been published, it is expected to be pathogenic, as loss of function variants in this gene are strongly associated with ARVC. Therefore, the presence of this variant in an individual indicates that the individual is likely at increased risk to develop this disorder.
Invitae RCV000464940 SCV000545237 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-10-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val280Hisfs*55) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. 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 an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705). ClinVar contains an entry for this variant (Variation ID: 202015). Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic.
Gharavi Laboratory,Columbia University RCV000505802 SCV000809451 pathogenic not provided 2018-09-16 no assertion criteria provided research

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