ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.327A>G (p.Ile109Met) (rs373305929)

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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 RCV000039433 SCV000063117 likely benign not specified 2017-01-20 criteria provided, single submitter clinical testing p.Ile109Met in exon 3 of DSC2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 5 mammals (Alpaca, Horse, Bat, Microbat and Elephant) have a methionine (Met ) at this position. Of note, this variant has been reported by our laboratory in 1 Asian individual with ARVC (LMM data, Palmisano 2011), however, this individu al carried an additional variant likely to explain disease (c.2489+1G>A in PKP2) . This p.Ile109Met has also been reported in ClinVar (Variation ID:46190). Final ly, it has also been identified in 1/16454 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373305929) .
GeneDx RCV000766855 SCV000233413 uncertain significance not provided 2018-05-21 criteria provided, single submitter clinical testing The I109M variant of uncertain significance in the DSC2 gene has been previously reported in a father and son who both had ARVD/C, however, they both also harbored a pathogenic splice site variant in the PKP2 gene and additional segregation studies in other relatives were not described (Palmisano et al., 2011). This variant has also been observed in other individuals referred for cardiomyopathy genetic testing at GeneDx, although these individuals harbored additional cardiogenetic variants and no segregation data are available to further clarify the role of this variant in disease. The I109M variant is also observed in 6/111306 (0.005%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Additionally, I109M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625301 SCV000744771 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2015-09-21 criteria provided, single submitter clinical testing
Invitae RCV000625301 SCV000766335 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2017-12-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 109 of the DSC2 protein (p.Ile109Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs373305929, ExAC 0.006%). This variant has been observed in an individual with arrhythmogenic right ventricular cardiomyopathy, as well as the affected father (PMID: 21822014). However, in these individuals a pathogenic allele was also identified in PKP2, which suggests that this c.327A>G variant may not be the primary cause of disease. 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, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000777975 SCV000914080 uncertain significance Cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the propeptide domain of the DSC2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been observed in an individual with arrhythmogenic right ventricular cardiomyopathy, as well as in the affected father (PMID: 21822014). However, these individuals also carried a pathogenic splice variant in PKP2, suggesting that this missense variant may not be the primary cause of disease in this family. This variant has been identified in 9/245638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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