Submissions for variant NM_024422.6(DSC2):c.743_748del (p.Tyr248_Thr249del)

dbSNP: rs776784065

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221635	SCV000271709	uncertain significance	not specified	2015-07-02	criteria provided, single submitter	clinical testing	The p.Tyr248_Thr249del variant in DSC2 has not been previously reported in indiv iduals with cardiomyopathy and data from large population studies is insufficien t to assess the frequency of this variant. This variant is a deletion of 2 amino acids starting at position 248 and is not predicted to alter the protein readin g-frame. It is unclear if this deletion will impact the protein. In summary, the clinical significance of the p.Tyr248_Thr249del variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000285235	SCV000408104	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000658360	SCV000780132	uncertain significance	not provided	2018-05-23	criteria provided, single submitter	clinical testing	The c.743_748delATACTT variant of uncertain significance in the DSC2 gene has not been published as pathogenic or been reported as benign to our knowledge. The c.743_748delATACTT variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant results in an in-frame deletion of two amino acids (tyrosine and threonine) at codons 248 and 249, denoted p.Tyr248_Thr249del, and does not result in a shift in reading frame or a premature stop codon. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, two other in-frame deletions in the DSC2 gene have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Nevertheless, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.
Invitae	RCV001853446	SCV002198174	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-10-06	criteria provided, single submitter	clinical testing	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant, c.743_748del, results in the deletion of 2 amino acid(s) of the DSC2 protein (p.Tyr248_Thr249del), but otherwise preserves the integrity of the reading frame. This variant has not been reported in the literature in individuals affected with DSC2-related conditions. 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. ClinVar contains an entry for this variant (Variation ID: 228626).
New York Genome Center	RCV001853446	SCV002764390	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-10-06	criteria provided, single submitter	clinical testing	The c.743_748del variant identified in the DSC2 gene is predicted to result in deletion of two amino acids (p.(Tyr248_Thr249del)) that are located in the extracellular Cadherin 2 domain of the encoded protein without causing a shift in the reading frame (in-frame deletion). This variant is observed in three individuals across population databases (gnomAD v2.1.1 and v3.1.1, TOPMed Freeze 5) suggesting it is not a common benign variant in the populations represented in those databases. This variant has not been reported in the literature before, however, it has been reported three times in ClinVar as Variant of Uncertain Significance(ClinVar ID: 228626). Additionally, this variant was reported to be found in trans with the p.(Phe250Ser) variant in an individual with Arrhythmogenic right ventriculardysplasia 11 (ClinVar ID: 523128). Two single nucleotide variants and one deletion-insertion variant that are predicted to result in a missense variation at the residue p.Thr249 have also been reported six times in ClinVar as Variants of Unknown Significance (ClinVar IDs: 199763, 920996, 960002). In silico predictions are not applicable to this variant. Based on the available evidence the c.743_748del (p.(Tyr248_Thr249del)) variant identified in the DSC2 gene is reported as Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV003997727	SCV004838227	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-11-20	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of two amino acids (p.Tyr248_Thr249del) in the DSC2 protein. 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 1/250810 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.