Submissions for variant NM_001005242.3(PKP2):c.1063C>T (p.Arg355Ter)

gnomAD frequency: 0.00001  dbSNP: rs754912778

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183731	SCV000236211	pathogenic	not provided	2023-06-16	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 24125834, 31402444, 35653365, 35536239, 28491739, 36451335, 25765472)
Invitae	RCV001218972	SCV001390884	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg355*) 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 (rs754912778, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 25765472, 27532257). ClinVar contains an entry for this variant (Variation ID: 201977). For these reasons, this variant has been classified as Pathogenic.
New York Genome Center	RCV001218972	SCV002548797	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-07-16	criteria provided, single submitter	clinical testing	The nonsense c.3764C>G, p.Ala1255Gly variant identified in the MYBPC3 gene has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 27532257, 25765472). This variant is absent in gnomAD v3.1.1, suggesting it is not a common benign variant in the populations represented in this database. The variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNAdecay. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). Based on available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003996831	SCV004839359	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-11-28	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. It has been reported in multiple individuals with arrhythmogenic right ventricular cardiomyopathy or referred for cardiomyopathy genetic testing (PMID: 28491739, 25765472, 24125834, 27532257). This variant is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003996831	SCV004848060	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2019-03-29	criteria provided, single submitter	clinical testing	The p.Arg355X variant in PKP2 has been identified in 1 individual with ARVC (Bao 2013). This variant has also been identified in 1/8650 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs754912778) and has been reported in ClinVar (Variation ID: 201977). This nonsense variant leads to a premature termination codon at position 355, which is predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in PKP2 are strongly associated with ARVC. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg355X variant is likely pathogenic.
Ambry Genetics	RCV004020235	SCV005022527	pathogenic	Cardiovascular phenotype	2023-12-01	criteria provided, single submitter	clinical testing	The p.R355* pathogenic mutation (also known as c.1063C>T), located in coding exon 4 of the PKP2 gene, results from a C to T substitution at nucleotide position 1063. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Zhou X et al. Eur J Med Genet, 2015 Apr;58:258-65; Castro SA et al. HeartRhythm Case Rep, 2016 Nov;2:469-472). This alteration has also been reported in biobank and whole exome sequencing cohorts (Haggerty CM et al. Genet Med, 2017 Nov;19:1245-1252; Xiao H et al. World J Pediatr, 2022 Oct;18:687-694; Bourfiss M et al. Circ Genom Precis Med, 2022 Dec;15:e003704). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.