ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.3353C>T (p.Ser1118Phe) (rs368703304)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479999 SCV000564949 uncertain significance not provided 2018-09-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSG2 gene. The S1118F variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in conjunction with additional cardiogenetic variants in other individuals referred for cardiomyopathy genetic testing at GeneDx, although no segregation data are available to further clarify the role of this variant in disease. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S1118F 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. Additionally, this substitution occurs at a position where amino acids with similar properties to serine (S) are tolerated across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000537280 SCV000641984 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-09-25 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 1118 of the DSG2 protein (p.Ser1118Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs368703304, ExAC 0.02%) but has not been reported in the literature in individuals with a DSG2-related disease. 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: Possibly Damaging; Align-GVGD: Class C1). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV001177921 SCV001342234 uncertain significance Cardiomyopathy 2019-05-21 criteria provided, single submitter clinical testing

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