Submissions for variant NM_001005242.3(PKP2):c.1968A>T (p.Glu656Asp)

gnomAD frequency: 0.00003  dbSNP: rs879210282

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537743	SCV000638880	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-06-14	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 464419). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 700 of the PKP2 protein (p.Glu700Asp).
Color Diagnostics, LLC DBA Color Health	RCV001188385	SCV001355441	uncertain significance	Cardiomyopathy	2020-08-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 700 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 not been reported in individuals affected with cardiovascular disorders in the literature. 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.
GeneDx	RCV002245003	SCV002513686	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy (Mazzarotto et al., 2020); however, specific clinical information was not provided; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31983221)
Ambry Genetics	RCV002420426	SCV002728352	uncertain significance	Cardiovascular phenotype	2021-02-01	criteria provided, single submitter	clinical testing	The p.E700D variant (also known as c.2100A>T), located in coding exon 10 of the PKP2 gene, results from an A to T substitution at nucleotide position 2100. The glutamic acid at codon 700 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was reported in one individual from a dilated cardiomyopathy (DCM) cohort; however clinical details were limited (Mazzarotto F et al. Circulation, 2020 02;141:387-398). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.