Submissions for variant NM_001943.5(DSG2):c.3039C>A (p.Tyr1013Ter)

gnomAD frequency: 0.00003  dbSNP: rs539821357

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000431080	SCV000535422	uncertain significance	not provided	2020-11-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation as the last 106 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 31931689, 31983221)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642320	SCV000763989	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1013*) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 106 amino acid(s) of the DSG2 protein. This variant is present in population databases (rs539821357, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 392196). This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1020Alafs*18) have been determined to be pathogenic (PMID: 20864495, 21397041, 23381804). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769518	SCV000900913	uncertain significance	Cardiomyopathy	2016-11-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769518	SCV001343658	uncertain significance	Cardiomyopathy	2023-03-22	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 15 of the DSG2 gene, creating a premature translation stop signal in the last coding exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 34500006). This variant has been identified in 18/280770 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.
Ambry Genetics	RCV003298456	SCV003996697	uncertain significance	Cardiovascular phenotype	2023-03-27	criteria provided, single submitter	clinical testing	The p.Y1013* variant (also known as c.3039C>A), located in coding exon 15 of the DSG2 gene, results from a C to A substitution at nucleotide position 3039. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theDSG2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 9% of the protein. The exact functional effect of this alteration is unknown. Additionally, based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.