Submissions for variant NM_001005242.3(PKP2):c.1132C>T (p.Gln378Ter)

gnomAD frequency: 0.00001  dbSNP: rs397516986

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211737	SCV000061815	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2018-10-24	criteria provided, single submitter	clinical testing	The p.Gln378X variant in PKP2 has been identified in >15 individuals with ARVC ( Watkins 2009, Fressart 2010, Bhonsale 2013, Kumar 2013 Ohno 2013, Kumar 2013, Ph ilips 2014, Groeneweg 2015, Torkamani 2016, Sonoda 2017, Wada 2017, Orgeron 2017 , LMM data) and was reported to be de novo in 1 case (Horie 2008). It has also b een reported by other clinical laboratories in ClinVar (Variation ID # 45010) an d has been identified in 2/129154 European chromosomes by gnomAD (http://gnomad. broadinstitute.org). This nonsense variant leads to a premature termination codo n at position 378, which is predicted to lead to a truncated or absent protein. Loss of function of the PKP2 gene is an established disease mechanism in in indi viduals autosomal dominant ARVC. In summary, this variant meets criteria to be c lassified as pathogenic for autosomal dominant ARVC. ACMG/AMP criteria applied: PVS1, PS4, PM2, PM6.
GeneDx	RCV000183735	SCV000236215	pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Reported in multiple unrelated individuals from different ethnic backgrounds in association with ARVC (Watkins et al., 2009; Fressart et al., 2010; Bhonsale et al., 2013; Ohno et al., 2013; Philips et al., 2014; Groeneweg et al., 2015; Torkamani et al., 2016; Walsh et al., 2017; Sonoda et al., 2017; Wada et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); Nonsense 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: 24585727, 34120153, 23973953, 28588093, 31386562, 31402444, 19880068, 20400443, 23514727, 23671136, 27727376, 27532257, 28431057, 25820315, 29178656, 30790397, 33087929)
Ambry Genetics	RCV000621345	SCV000734875	pathogenic	Cardiovascular phenotype	2019-12-26	criteria provided, single submitter	clinical testing	The p.Q378* pathogenic mutation (also known as c.1132C>T), located in coding exon 4 of the PKP2 gene, results from a C to T substitution at nucleotide position 1132. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration has been reported in multiple unrelated individuals with confirmed or suspected arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (Philips B et al. Circ Arrhythm Electrophysiol. 2014;7(2):230-6; Kumar S et al. Heart Rhythm. 2013; 10(11):1653-60; Ohno S et al. Circ J. 2013;77(6):1534-42; Fressart V et al. Europace. 2010;12(6):861-8; Watkins DA et al. Heart Rhythm. 2009;6(11 Suppl):S10-7). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798628	SCV000938253	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln378*) 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 present in population databases (rs397516986, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 19880068, 23514727, 27532257). ClinVar contains an entry for this variant (Variation ID: 45010). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000798628	SCV000996041	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2019-07-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001179300	SCV001343931	pathogenic	Cardiomyopathy	2022-06-21	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 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 more than 15 individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 19880068, 20400443, 23514727, 23671136, 24585727, 25820315, 27532257, 27727376, 28431057, 28588093, 29178656). This variant has been identified in 2/282774 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000798628	SCV002018840	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2019-09-11	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000183735	SCV002501523	pathogenic	not provided	2021-11-09	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000798628	SCV002769083	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2022-02-02	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 (ARVD9; MIM#609040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17010805, 23183494). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 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 (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to cause NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700308	SCV005203274	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2024-07-08	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1132C>T (p.Gln378X) 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 251360 control chromosomes. c.1132C>T has been reported in the literature in at least one individual affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Ohno_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23514727). ClinVar contains an entry for this variant (Variation ID: 45010). Based on the evidence outlined above, the variant was classified as pathogenic.