ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.548G>A (p.Ser183Asn) (rs373222905)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455365 SCV000540046 uncertain significance not specified 2016-12-16 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: This variant is classified in HGMD as DM, related to Brugada syndrome and reported in one patient with spontaneous ECG pattern during febrile episode. An in vitro construct with this variant showed that the mutant cells could not rescue the knockdown of PKP2 and that this mutant leads to decreased sodium current. This variant is classified in ClinVar with 1 star as Pathogenic by GeneDx. The variant has a Max MAF of 0.015% in ExAC (1 allele) and 0.1% in gnomAD (10 Ashkenazi alleles). It is predicted to be benign by prediction tools. 3 mammals and 6 non-mammals have an Asn at this position.
Color RCV000772019 SCV000904975 uncertain significance Cardiomyopathy 2020-03-12 criteria provided, single submitter clinical testing
Invitae RCV000822207 SCV000962998 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 183 of the PKP2 protein (p.Ser183Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs373222905, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals with clinical features of Brugada syndrome (PMID: 24352520, 25998140). ClinVar contains an entry for this variant (Variation ID: 201974). Experimental studies have shown that this missense change decreases sodium channel function (PMID: 24352520). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000994892 SCV001148700 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000822207 SCV001271391 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-04-28 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.

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