ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2603C>T (p.Ser868Phe) (rs141873745)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics,University of Leuven RCV000497924 SCV000579556 uncertain significance Hypertrophic cardiomyopathy 2017-04-30 criteria provided, single submitter clinical testing
GeneDx RCV000520921 SCV000618029 uncertain significance not provided 2017-07-13 criteria provided, single submitter clinical testing The S868F variant in the DSC2 gene has been reported previously in an individual with arrhythmogenic right ventricular cardiomyopathy and in individuals with sudden cardiac death, however, these individuals also harbored variants in other cardiac-related genes that may also have contributed to the phenotype (Fressart et al., 2010; Nunn et al., 2016; Sanchez et al., 2016). The S868F variant is observed in 5/66,698 (0.0075%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The S868F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S868F as a variant of uncertain significance.
Invitae RCV000704414 SCV000833363 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 868 of the DSC2 protein (p.Ser868Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs141873745, ExAC 0.02%). This variant has been reported in several individuals affected with arrhythmogenic right ventricular cardiomyopathy or sudden death (PMID: 20400443, 26498160, 27930701). However, in one of these individuals, a pathogenic allele was also identified in PKP2, which suggests that this c.2603C>T variant was not the primary cause of disease, while the other individuals were also reported to have variants in other genes. ClinVar contains an entry for this variant (Variation ID: 427964). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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