Submissions for variant NM_001005242.3(PKP2):c.1379-2018G>A

gnomAD frequency: 0.00013  dbSNP: rs369518480

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218353	SCV000272306	uncertain significance	not specified	2016-01-26	criteria provided, single submitter	clinical testing	The p.Arg490Gln variant in PKP2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/13418 South Asian chromosomes and 2/6462 African chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs369518480). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, tho ugh this information is not predictive enough to rule out pathogenicity. In summ ary, the clinical significance of the p.Arg490Gln variant is uncertain.
Invitae	RCV000640002	SCV000761589	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 490 of the PKP2 protein (p.Arg490Gln). This variant is present in population databases (rs369518480, gnomAD 0.02%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 229143). 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.
Color Diagnostics, LLC DBA Color Health	RCV001175623	SCV001339292	uncertain significance	Cardiomyopathy	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 490 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 performed for this variant. This variant has been reported in a sudden unexplained deaths cohort (PMID: 29247119). This variant has been identified in 16/261928 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	RCV002390585	SCV002701585	likely benign	Cardiovascular phenotype	2020-12-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Fulgent Genetics, Fulgent Genetics	RCV000640002	SCV002779447	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2021-12-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000640002	SCV003808499	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2020-01-29	criteria provided, single submitter	clinical testing