Submissions for variant NM_001005242.3(PKP2):c.2332A>G (p.Ile778Val)

gnomAD frequency: 0.00006  dbSNP: rs145324631

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208084	SCV000264146	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-11-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464399	SCV000545243	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 822 of the PKP2 protein (p.Ile822Val). This variant is present in population databases (rs145324631, gnomAD 0.006%). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 32553227). ClinVar contains an entry for this variant (Variation ID: 188664). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000168939	SCV000565378	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32553227)
Illumina Laboratory Services, Illumina	RCV000464399	SCV001272953	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV001183988	SCV001349850	uncertain significance	Cardiomyopathy	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 822 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 an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 32553227). This variant has been identified in 11/282834 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.
Ambry Genetics	RCV002453566	SCV002738227	uncertain significance	Cardiovascular phenotype	2024-09-27	criteria provided, single submitter	clinical testing	The c.2464A>G (p.I822V) alteration is located in exon 12 (coding exon 12) of the PKP2 gene. This alteration results from a A to G substitution at nucleotide position 2464, causing the isoleucine (I) at amino acid position 822 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000208084	SCV004845905	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 822 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 an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 32553227). This variant has been identified in 11/282834 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.