Submissions for variant NM_001005242.3(PKP2):c.1379-2012C>T

gnomAD frequency: 0.00002  dbSNP: rs760461056

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001115121	SCV001273069	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2017-04-27	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.
Color Diagnostics, LLC DBA Color Health	RCV001177632	SCV001341873	uncertain significance	Cardiomyopathy	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 492 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 Brugada syndrome and in an individual over 65 years of age with no history of cardiac arrhythmia (PMID: 25650408). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001115121	SCV002303020	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2022-07-03	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 492 of the PKP2 protein (p.Thr492Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PKP2-related conditions (PMID: 25650408; Invitae). ClinVar contains an entry for this variant (Variation ID: 884170). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine 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.
Ambry Genetics	RCV002393361	SCV002698068	likely benign	Cardiovascular phenotype	2023-08-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV004000246	SCV004846392	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 492 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 Brugada syndrome and in an individual over 65 years of age with no history of cardiac arrhythmia (PMID: 25650408). This variant has not been identified 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.