ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1901del (p.Asn634fs) (rs1064793231)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484313 SCV000565377 pathogenic not provided 2017-02-27 criteria provided, single submitter clinical testing The c.1901delA pathogenic variant in the PKP2 gene has previously been reported in a 16 year-old male who experienced sudden unexpected death while playing football (Anderson et al., 2016). This variant causes a shift in reading frame starting at codon Asparagine 634, changing it to a Threonine, and creating a premature stop codon at position 22 of the new reading frame, denoted p.Asn634ThrfsX22. This pathogenic 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 Human Gene Mutation Database in association with ARVC/D (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.1901delA variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV001067162 SCV001232205 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn634Thrfs*22) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy or sudden unexplained death (PMID: 27532257, 27114410). ClinVar contains an entry for this variant (Variation ID: 418411). Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic.

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