Submissions for variant NM_001005242.3(PKP2):c.1138G>T (p.Glu380Ter)

dbSNP: rs878898365

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589832	SCV000698459	likely pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2017-05-09	criteria provided, single submitter	clinical testing	Variant summary: The PKP2 c.1138G>T (p.Glu380X) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 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 (e.g. c.1237C>T, p.Arg413X; c.1613G>A, p.Trp538X; c.1912C>T, p.Gln638X; c.2013delC, p.Lys672fsX12). Mutation taster predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 121400 control chromosomes. The variant of interest has not been reported in peer-reviewed publications and/or by clinical diagnostic laboratories. ARVC and LOVD databases report this variant citing a poster material published in a journal (Tsatsopoulou et al. European Heart Journal 2007;28:Suppl; 382) in one proband with TCF positive ARVC who had positive family history of disease with five affected relatives. Both databases have classified it as pathogenic. Taken together, this variant is classified as likely pathogenic.
Ambry Genetics	RCV000621081	SCV000734878	pathogenic	Cardiovascular phenotype	2024-10-15	criteria provided, single submitter	clinical testing	The p.E380* pathogenic mutation (also known as c.1138G>T), located in coding exon 4 of the PKP2 gene, results from a G to T substitution at nucleotide position 1138. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
CeGaT Center for Human Genetics Tuebingen	RCV002061981	SCV002497213	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	PKP2: PVS1, PM2, PS4:Moderate
Color Diagnostics, LLC DBA Color Health	RCV003532181	SCV004358899	pathogenic	Cardiomyopathy	2023-08-03	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 in the armadillo repeat 1 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy and sudden cardiac arrest (PMID: 28472724). 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.
All of Us Research Program, National Institutes of Health	RCV004002440	SCV004830320	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2024-08-23	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 in the armadillo repeat 1 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy and sudden cardiac arrest (PMID: 28472724). 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.