Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000485089 | SCV000564948 | likely pathogenic | not provided | 2017-03-16 | criteria provided, single submitter | clinical testing | A c.2358delA variant that is likely pathogenic was identified in the DSG2 gene. This variant has been reported in two individuals enrolled in a study for the use of buccal mucosa cells from ARVC/D patients to characterize disease mechanism and possible effective therapies (Asimaki et al., 2016). This variant causes a shift in reading frame starting at codon Asparagine 787, changing it to a Methionine, and creating a premature stop codon at position 21 of the new reading frame, denoted p.Asp787MetfsX21. The likely pathogenic variant is expected to result in an abnormal, truncated protein product where the last 332 amino acids of DSG2 are replaced with 20 incorrect amino acids. Many other frameshift variants in the DSG2 gene have been reported in Human Gene Mutation Database in association with ARVC/D (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.2358delA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server),indicating it is not a common benign variant in these populations. The observation of this variant in other families with a similar phenotype, segregation analysis, and functional evidence, would further support this variant being pathogenic.In summary, c.2358delA in the DSG2 gene is interpreted as a likely pathogenic variant. |