ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.880A>G (p.Lys294Glu) (rs752432726)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455978 SCV000539031 uncertain significance not specified 2016-03-28 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: 1 report, functional study does not predict impact; ExAC: 1/9800 African chromosomes
Invitae RCV000642318 SCV000763987 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2017-11-16 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 294 of the DSG2 protein (p.Lys294Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs752432726, ExAC 0.01%). This variant has been reported in individuals affected with right ventricular cardiomyopathy (PMID: 16505173, 24070718). ClinVar contains an entry for this variant (Variation ID: 199803). Experimental studies using a human cell model have shown that this missense change did not cause a deleterious effect on protein function (PMID: 23071725). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757178 SCV000885314 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing The DSG2 c.880A>G; p.Lys294Glu variant (rs752432726; ClinVar ID 199803) has been reported in a single individual with arrhythmogenic right ventricular cardiomyopathy (Pilichou 2006); however, functional studies of this variant found no defects in prodomain cleavage, adhesion properties, or cellular localization compared to the wild-type protein (Gaertner 2012). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.002% (identified on 6 out of 277,042 chromosomes). The lysine at position 294 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Lys294Glu variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Lys294Glu variant cannot be determined with certainty.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845343 SCV000987390 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy criteria provided, single submitter clinical testing
Color Health, Inc RCV001177919 SCV001342231 uncertain significance Cardiomyopathy 2020-11-17 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 294 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not impact prodomain cleavage, cellular localization, adhesion and protein binding properties of DSG2 protein (PMID: 23071725, 30885746). This variant has been reported in several individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718). This variant has also been identified in 6/280794 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000757178 SCV001712936 uncertain significance not provided 2020-01-10 criteria provided, single submitter clinical testing

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