ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1689dup (p.Val564fs) (rs397517010)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038187 SCV000061854 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2018-02-20 criteria provided, single submitter clinical testing The p.Val608fs variant in PKP2 has been reported in 2 individuals with clinical features of ARVC (Bhonsale 2013, LMM unpublished data). This variant has been id entified in 1/111470 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397517010) and has been previ ously reported in ClinVar (Variation ID 45047). This variant is predicted to cau se a frameshift, which alters the protein?s amino acid sequence beginning at pos ition 608 and leads to a premature termination codon 6 amino acids downstream. T his alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the PKP2 gene is an established disease mechanism in ARVC. In summary, although additional studies are required to fully establish i ts clinical significance, the p.Val608fs variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2; PS4_S (Richards 2015).
Ambry Genetics RCV000242219 SCV000320675 pathogenic Cardiovascular phenotype 2016-01-02 criteria provided, single submitter clinical testing
Invitae RCV000640015 SCV000761602 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-02-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val608Cysfs*6) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs397517010, ExAC 0.001%). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28588093, Invitae). ClinVar contains an entry for this variant (Variation ID: 45047). Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000640015 SCV000840043 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-04-25 criteria provided, single submitter clinical testing This c.1821_1822insT (p.Val608Cysfs*6) variant in the PKP2 gene has not been reported previously while observed with extremely low allele frequency in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.1821_1822insT (p.Val608Cysfs*6) variant in the PKP2 gene is classified as likely pathogenic.
GeneDx RCV001008767 SCV001168555 pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing The c.1821dupT pathogenic variant in the PKP2 gene has been reported previously in association with ARVC (Bhonsale et al., 2013; Bhonsale et al., 2015; Groeneweg et al., 2015; te Riele et al, 2015; Orgeron et al., 2017). This variant causes a shift in reading frame starting at codon valine 608, changing it to a cysteine, and creating a premature stop codon at position 6 of the new reading frame, denoted p.Val608CysfsX6. This variant is expected to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other frameshift variants in the PKP2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.1821dupT variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016).
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171163 SCV001333848 likely pathogenic Cardiomyopathy 2019-03-14 criteria provided, single submitter clinical testing

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