ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2298G>C (p.Gln766His) (rs139558481)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181162 SCV000233439 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSC2 gene. The Q766H variant has not been published in association with cardiomyopathy to our knowledge, but has been identified in two cases from a cohort of 22 Ethiopian patients with ichthyosis vulgaris and atopic dermatitis (Taylan et al., 2015), however, further clinical details were not available and potential cardiac findings were not specified. This variant has also been reported in one other individual referred for cardiomyopathy genetic testing at GeneDx, although other variants were also detected and no segregation data are available to further clarify the role of this variant in disease. Additionally, Q766H is observed at a global allele frequency of 14/276788 (0.005%) alleles in large population cohorts, including 7/24032 (0.029%) alleles from individuals of African ancestry (Lek et al., 2016). Finally, while Q766H is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000693608 SCV000821483 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-05-04 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 766 of the DSC2 protein (p.Gln766His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs139558481, ExAC 0.03%). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 199772). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine 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.

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