Submissions for variant NM_001005242.3(PKP2):c.1368del (p.Lys456fs)

dbSNP: rs1393661338

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174751	SCV001338068	likely pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2020-01-13	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1368delA (p.Lys456AsnfsX3) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250950 control chromosomes. c.1368delA has been reported in the literature in at-least one individual affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Dalal_2006) and has subsequently been cited in other studies reporting authorship and/or institutional overlap (example, denHaan_2009, Zu_2010). These data support the notion that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873651	SCV002155801	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2022-08-09	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys456Asnfs*3) 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, 23911551). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 917646). This variant is also known as p.Asn456fs*458 and K456NfsX458. This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 31386562).
Ambry Genetics	RCV002379674	SCV002700300	pathogenic	Cardiovascular phenotype	2021-08-10	criteria provided, single submitter	clinical testing	The c.1368delA pathogenic mutation, located in coding exon 5 of the PKP2 gene, results from a deletion of one nucleotide at nucleotide position 1368, causing a translational frameshift with a predicted alternate stop codon (p.K456Nfs*3). This alteration has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts, including in a family in which this alteration was inherited from an unaffected mother (Dalal D et al. Circulation, 2006 Apr;113:1641-9; Xu T et al. J Am Coll Cardiol, 2010 Feb;55:587-97). 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.
All of Us Research Program, National Institutes of Health	RCV004000283	SCV004839103	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This variant causes deletion of 1 nucleotide in exon 5 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy/dysplasia (PMID: 16549640, 20031617, 20152563, 20857253, 23671136, 25820315, 28588093, 31386562), including in one individual who inherited the variant from an unaffected mother (PMID: 20152563). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.