Submissions for variant NM_001005242.3(PKP2):c.253_256del (p.Glu85fs)

dbSNP: rs786204388

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412778	SCV000490723	pathogenic	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 30731207, 27532257, 20400443, 24125834, 26314686, 25820315, 28588093, 26850880, 30790397, 30571190, 32268277, 30700137, 31386562, 31402444, 34135346, no PMID, 35819174, 35536239)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000999610	SCV001156314	likely pathogenic	Sudden unexplained death	2018-02-09	criteria provided, single submitter	research	PKP2 Glu85Metfs*26 has been previously reported in 1 ARVC patient (Fressart V, et al., 2010). We identified this variant in a case of sudden unexplained death in a young male. Genetic testing in this individual also identified two other variants (CASQ2 Phe189Leu & NEBL Gln682Ter). The variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/).Based on rarity in the general population and because loss of function variants in PKP2 is an established mechanism of disease, we classify PKP2 Glu85Metfs*26 as "likely pathogenic".
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389964	SCV001591526	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu85Metfs*26) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy and/or those who suffered sudden death (PMID: 20400443, 27532257, 30571190, 30700137). ClinVar contains an entry for this variant (Variation ID: 188653). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798606	SCV002043319	pathogenic	Cardiomyopathy	2022-05-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426802	SCV002742403	pathogenic	Cardiovascular phenotype	2019-09-19	criteria provided, single submitter	clinical testing	The c.253_256delGAGT pathogenic mutation, located in coding exon 2 of the PKP2 gene, results from a deletion of 4 nucleotides at nucleotide positions 253 to 256, causing a translational frameshift with a predicted alternate stop codon (p.E85Mfs*26). This alteration has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) and sudden cardiac death cohorts (Fressart V et al. Europace, 2010 Jun;12:861-8; Walsh R et al. Genet. Med., 2017 02;19:192-203; Miles C et al. Circulation, 2019 Apr;139:1786-1797). In addition to the clinical data presented in the literature, 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001389964	SCV002766760	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 9 (MIM#609040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMIDs: 17010805, 23183494). (I) 0115 - Variants in this gene are known to have variable expressivity (PMIDs: 17010805, 23183494). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic/pathogenic in individuals with arrhythmogenic right ventricular cardiomyopathy or sudden cardiac arrest (ClinVar, PMIDs: 27532257, 30677492, 30678776), and also in asymptomatic individuals (PMIDs: 30678776, 34135346). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign