ClinVar Miner

Submissions for variant NM_001005242.2(PKP2):c.2377del (p.Ser793fs) (rs727504432)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154671 SCV000204349 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2017-07-21 criteria provided, single submitter clinical testing The p.Ser837fs variant in PKP2 has been reported in >10 individuals with clinica l features of ARVC (Gerull 2004, Dalal 2006, Dalal 2006, Dalal 2009, Xu 2010, An toniades 2006, Fressart 2009, Barahona-Dussault 2010, Den Haan 2009, Watkins 200 9, Tan, 2010, Cox 2011, Baskin 2013) and was absent from large population studie s. It has also been reported by other clinical laboratories in ClinVar (Variatio n ID 177995). This variant causes a frameshift, which is predicted to replace th e last 45 amino acid residues of the protein with 93 aberrant residues. This alt eration is predicted to lead to an elongated protein with a termination codon th at is 94 amino acids downstream of the frameshift. In summary, although addition al functional studies are required to fully establish its clinical significance, the p.Ser837fs variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS 4_M, PM4 (Richards 2015).
GeneDx RCV000183778 SCV000236259 pathogenic not provided 2018-12-17 criteria provided, single submitter clinical testing The c.2509delA pathogenic variant in PKP2 causes a shift in reading frame starting at codon Serine 837, changing it to a Valine, and replaces the last 45 amino acid residues of the protein with 93 aberrant residues, thus altering and extending the resulting protein product. The c.2509delA pathogenic variant in the PKP2 gene has been previously reported in multiple unrelated individuals diagnosed with ARVC (Gerull B et al., 2004; Dalal D et al., 2006; Antoniades L et al., 2006; Watkins D et al., 2009; Barahona-Dussault C et al., 2010; Fressart V et al., 2010). Considering all publications, the c.2509delA pathogenic variant was not detected in more than 1,500 control alleles, indicating it is not a common benign variant in the general population (Gerull B et al., 2004; Watkins D et al., 2009; Fressart V et al., 2010). The c.2509delA pathogenic variant has been seen in other unrelated individuals at GeneDx. In summary, c.2509delA in the PKP2 gene is interpreted as a disease-causing pathogenic variant.
Ambry Genetics RCV000251945 SCV000320265 pathogenic Cardiovascular phenotype 2019-10-11 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence;Other strong data supporting pathogenic classification
Invitae RCV000470468 SCV000545235 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-11-06 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 13 of the PKP2 mRNA (c.2509delA), causing a frameshift at codon 837. This creates a translational stop signal in the last exon of the PKP2 mRNA (p.Ser837Valfs*94). While this is not anticipated to result in nonsense mediated decay, it results in an altered PKP2 protein. This variant is not present in population databases (rs727504432, ExAC no frequency). This variant has been reported to segregate with arrhythmogenic right ventricular cardiomyopathy in family (ARVC) (PMID: 17010805). It has also been observed in numerous unrelated individuals affected with ARVC (PMID: 15489853, 24585727, 21606396, 23871674, 20031617, 19880068, 16893920, 16549640, 20152563). ClinVar contains an entry for this variant (Variation ID: 177995). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000154671 SCV000748003 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2017-05-07 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852448 SCV000995140 pathogenic Ventricular tachycardia 2018-09-15 criteria provided, single submitter clinical testing
Color RCV001191916 SCV001359851 pathogenic Cardiomyopathy 2020-02-07 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.