Submissions for variant NM_001005242.3(PKP2):c.2302G>A (p.Asp768Asn)

gnomAD frequency: 0.00009  dbSNP: rs200947767

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455220	SCV000540043	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only probands are compound hets; ExAC: 2/8654 East Asian chromosomes
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623568	SCV000740393	uncertain significance	Left ventricular noncompaction	2016-11-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000772018	SCV000904974	uncertain significance	Cardiomyopathy	2023-07-28	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 812 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two Japanese individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 22214898). One of them was a compound heterozygote who also carried a pathogenic variant c.2489+1G>A in the same gene. This variant has also been identified in 15/282856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001115021	SCV001272954	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2018-08-21	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001115021	SCV001413854	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 812 of the PKP2 protein (p.Asp812Asn). This variant is present in population databases (rs200947767, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 22214898). ClinVar contains an entry for this variant (Variation ID: 403313). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001574174	SCV001800939	uncertain significance	not provided	2021-02-19	criteria provided, single submitter	clinical testing	Reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) who also harbor additional cardiogenetic variants (Nakajima et al., 2012); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 403313; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31402444, 22214898, 21636032, 23299917)
Ambry Genetics	RCV002451058	SCV002737210	uncertain significance	Cardiovascular phenotype	2023-08-29	criteria provided, single submitter	clinical testing	The p.D812N variant (also known as c.2434G>A), located in coding exon 12 of the PKP2 gene, results from a G to A substitution at nucleotide position 2434. The aspartic acid at codon 812 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been detected in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), in individuals from an exome cohort without cardiac phenotypes provided, and in control populations (Nakajima T et al. Circ. J., 2012 Dec;76:737-43; Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Kapplinger JD et al. J. Am. Coll. Cardiol., 2011 Jun;57:2317-27). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV001115021	SCV002779442	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2021-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455220	SCV003933776	uncertain significance	not specified	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.2434G>A (p.Asp812Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251480 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (4e-05 vs 0.00065), allowing no conclusion about variant significance. c.2434G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (examples: Kapplinger_2011, Nakajima_2012, Anderson_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23299917, 21636032, 22214898). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004000605	SCV004845912	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 812 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two Japanese individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 22214898). One of them was a compound heterozygote who also carried a pathogenic variant c.2489+1G>A in the same gene. This variant has also been identified in 15/282856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.