Submissions for variant NM_024422.6(DSC2):c.123del (p.Lys42fs)

dbSNP: rs1598592533

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008294	SCV001168062	likely pathogenic	not provided	2018-08-03	criteria provided, single submitter	clinical testing	Although the c.123delC likely pathogenic variant in the DSC2 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon lysine 42, changing it to an asparagine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Lys42AsnfsX2. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the DSC2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.123delC variant has not been observed in large population cohorts (Lek et al., 2016).
Invitae	RCV002549286	SCV003315162	pathogenic	Arrhythmogenic right ventricular dysplasia 11	2023-09-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817185). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys42Asnfs*2) in the DSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551).