Submissions for variant NM_001005242.3(PKP2):c.837_838del (p.Val280fs)

gnomAD frequency: 0.00001  dbSNP: rs772220644

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000505802	SCV000236266	pathogenic	not provided	2021-12-28	criteria provided, single submitter	clinical testing	Identified in a patient with arrhythmogenic right ventricular cardiomyopathy in published literature (Te Riele et al., 2017) and in individuals referred for genetic testing at GeneDx; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30677492, 28069705, 31447099, 31386562, 31402444)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464940	SCV000545237	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-11-04	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. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 17041889, 23911551). This variant is present in population databases (rs772220644, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705). ClinVar contains an entry for this variant (Variation ID: 202015). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000464940	SCV002018842	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2019-08-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165406	SCV003866283	pathogenic	Cardiovascular phenotype	2022-12-05	criteria provided, single submitter	clinical testing	The c.837_838delCG pathogenic mutation, located in coding exon 3 of the PKP2 gene, results from a deletion of two nucleotides at nucleotide positions 837 to 838, causing a translational frameshift with a predicted alternate stop codon (p.V280Hfs*55). This alteration has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts (Te Riele AS et al. Cardiovasc Res, 2017 Jan;113:102-111; Orgeron GM et al. J Am Heart Assoc, 2017 Jun;6:[ePub ahead of print]). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000464940	SCV004041229	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-05-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996844	SCV004831752	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-11-16	criteria provided, single submitter	clinical testing	The c.837_838del (p.Val280Hisfs*55) variant in the PKP2 gene creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been reported in at least three individuals (two individuals in digenic heterozygous status with a p.Arg406Gln variant in the DES gene) from the arrhythmogenic right ventricular cardiomyopathy/dysplasia cohorts (PMID: 28069705, 28588093, 30677492) and in one individual from an analytical cross-sectional study screening the ACMG59 gene, whose detailed phenotype is not described (PMID: 35803546). Loss of function variants are well known to be pathogenic for PKP2 (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Truncating variants downstream of this variant are reported to be pathogenic by several ClinVar submitters (ClinVar ID: 1693180, 1184949, 2040092, 1767649). This variant is found to be rare (2/282412; 0.000007) in the general population database (gnomAD) and interpreted as pathogenic by several (5) submitters in the ClinVar database (ClinVar ID: 202015). Therefore, the c.837_838del (p.Val280Hisfs*55) variant in the PKP2 gene is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003996844	SCV004848074	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2019-03-29	criteria provided, single submitter	clinical testing	The p.Val280fs variant in PKP2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/24030 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs772220644) and has been reported in ClinVar (Variantion ID: 202015). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 280 and leads to a premature termination codon 55 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in PKP2 are well-reported in individuals with ARVC (ARVD/C Genetic Variant Database, http://arvcdatabase.info; Human Gene Mutation Database). In summary, although additional studies are required to fully establish its clinical significance, the p.Val280fs variant is likely pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000464940	SCV005045693	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-06-14	criteria provided, single submitter	clinical testing	The c.837_838del (p.Val280Hisfs*55) variant in the PKP2 gene creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been reported in at least three individuals (two individuals in digenic heterozygous status with a p.Arg406Gln variant in the DES gene) from the arrhythmogenic right ventricular cardiomyopathy/dysplasia cohorts (PMID: 28069705, 28588093, 30677492) and in one individual from an analytical cross-sectional study screening the ACMG59 gene, whose detailed phenotype is not described (PMID: 35803546). Loss of function variants are well known to be pathogenic for PKP2 (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Truncating variants downstream of this variant are reported to be pathogenic by several ClinVar submitters (ClinVar ID: 1693180, 1184949, 2040092, 1767649). This variant is found to be rare (2/282412; 0.000007) in the general population database (gnomAD) and interpreted as pathogenic by several (5) submitters in the ClinVar database (ClinVar ID: 202015). Therefore, the c.837_838del (p.Val280Hisfs*55) variant in the PKP2 gene is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800320	SCV005423059	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2024-10-07	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.837_838delCG (p.Val280HisfsX55) 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. The variant allele was found at a frequency of 4e-06 in 251016 control chromosomes (gnomAD). c.837_838delCG has been reported in the literature in individuals affected with PKP2-related conditions (example: Dries_GM_2021). The following publication has been ascertained in the context of this evaluation (PMID: 34120153). ClinVar contains an entry for this variant (Variation ID: 202015). Based on the evidence outlined above, the variant was classified as pathogenic.
Gharavi Laboratory, Columbia University	RCV000505802	SCV000809451	pathogenic	not provided	2018-09-16	no assertion criteria provided	research