Submissions for variant NM_024422.6(DSC2):c.2412C>A (p.His804Gln)

dbSNP: rs1986728077

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174755	SCV001338072	uncertain significance	not specified	2020-01-13	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.2412C>A (p.His804Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251260 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2412C>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV002557502	SCV003328133	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-09-22	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with DSC2-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 917649). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 804 of the DSC2 protein (p.His804Gln).
All of Us Research Program, National Institutes of Health	RCV004000284	SCV004839029	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 804 of the DSC2 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 reported for this variant. This variant has not been reported in individuals affected with DSC2-related disorders in the literature. This variant has not been identified 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.