ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.3281_3283delinsTTA (p.Gly1094_His1095delinsValAsn) (rs386802145)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156648 SCV000206369 uncertain significance not specified 2014-07-10 criteria provided, single submitter clinical testing The Gly1094_His1095delinsValAsn variant in DSG2 has not been previously reported in individuals with cardiomyopathy. This variant is equivalent to 2 missense va riants (Gly1094Val and His1095Asn), though because they occur on the same copy o f the gene (in cis), they are described as above. Each missense variant has been identified in 3/3969 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs144313973 and rs140193292), though it is assumed that these actually represent this variant (dbSNP rs386802 145). This variant is a deletion of 2 amino acids at position 1094 and 1095 and an insertion of two different amino acids at these positions and is not predicte d to alter the protein reading-frame. While the affected amino acids are not wel l conserved, it is unclear if this variant will impact the protein. In summary, the clinical significance of the Gly1094_His1095delinsValAsn variant is uncertai n.
Invitae RCV000467438 SCV000551023 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-11-15 criteria provided, single submitter clinical testing This variant is a complex sequence change that results in the substitution of 2 amino acids of the DSG2 protein (p.Gly1094_His1095delinsValAsn). This variant is reported as two separate entries in the ExAC population database (c.3283C>A , 0.08% and c.3281G>T, 0.08%), and both have an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with a DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 179849). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587219 SCV000697888 uncertain significance not provided 2016-04-05 criteria provided, single submitter clinical testing Variant summary: The DSG2 c.3281_3283delinsTTA is equivalent to 2 missense variants (Gly1094Val and His1095Asn), but are described as a deletion/insertion variant because they occur on the same copy of the gene (in cis). Mutation Taster predicts a benign outcome for this variant; however, the variant has not been evaluated for functional impact by in vivo/vitro studies. Each missense variant has been identified in 10/120626 control chromosomes from the ExAC database (both in 8 Africans and 2 non-Finnish Europeans), and thus it is assumed that they actually represent this variant (dbSNP rs386802145). This is an allele frequency of 0.0000829, which is about 8 times greater than the maximal expected frequency of a pathogenic allele (0.00001), suggesting this variant is benign. [However, it cannot be confirmed that any of these occurrences were truly in cis.] Neither the variant of interest nor the individual missense variants has been reported in affected individuals via publications. One clinical lab has classified the variant of interest as a VUS in 2014, before the ExAC database was commonly used. Additionally, these amino acids are not conserved in mouse. Taken together, this variant was classified as a VUS-possibly benign variant until additional information is available.
Color Health, Inc RCV001179113 SCV001343713 uncertain significance Cardiomyopathy 2020-01-06 criteria provided, single submitter clinical testing

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