Submissions for variant NM_024422.6(DSC2):c.898A>G (p.Thr300Ala)

gnomAD frequency: 0.00002  dbSNP: rs531245154

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001192015	SCV001359958	uncertain significance	Cardiomyopathy	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 300 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 been identified in 4/251448 chromosomes 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.
Invitae	RCV001221688	SCV001393748	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-03-23	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 300 of the DSC2 protein (p.Thr300Ala). This variant is present in population databases (rs531245154, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 928242). 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 alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001192015	SCV004240496	uncertain significance	Cardiomyopathy	2022-11-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004010560	SCV004816195	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 300 of the DSC2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/251448 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.