Submissions for variant NM_024422.6(DSC2):c.1A>G (p.Met1Val)

dbSNP: rs1026402319

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001188139	SCV001355113	uncertain significance	Cardiomyopathy	2023-05-01	criteria provided, single submitter	clinical testing	This variant alters the translation initiation codon of the DSC2 mRNA. An alternate in-frame methionine downstream of the initiator methionine occurs at codon 144 in extracellular cadherin domain 1, after signal peptide and propeptide. This variant is expected to disrupt translation initiation and result in an absent or truncated protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with cardiac disease and sudden cardiac death (PMID: 31376648). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncations and other loss-of-function variants in the DSC2 gene have been reported in individuals with arrhythmogenic right ventricular cardiomyopathy. However, clinical significance of these variants is not yet fully understood. 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	RCV001337930	SCV001531550	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2020-09-20	criteria provided, single submitter	clinical testing	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 925908). This sequence change affects the initiator methionine of the DSC2 mRNA. The next in-frame methionine is located at codon 144.
All of Us Research Program, National Institutes of Health	RCV004010264	SCV004819398	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-01-11	criteria provided, single submitter	clinical testing	This variant alters the translation initiation codon of the DSC2 mRNA. An alternate in-frame methionine downstream of the initiator methionine occurs at codon 144 in extracellular cadherin domain 1, after signal peptide and propeptide. This variant is expected to disrupt translation initiation and result in an absent or truncated protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with cardiac disease and sudden cardiac death (PMID: 31376648). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncations and other loss-of-function variants in the DSC2 gene have been reported in individuals with arrhythmogenic right ventricular cardiomyopathy. However, clinical significance of these variants is not yet fully understood. 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.