Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000039441 | SCV000063125 | uncertain significance | not specified | 2012-07-20 | criteria provided, single submitter | clinical testing | The Tyr282His variant in DSC2 has not been reported in the literature nor previo usly identified in large and broad European American and African American popula tions by NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to est ablish this with confidence. Computational analyses (biochemical amino acid prop erties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to dete rmine pathogenicity. However, this variant is present in 2 reportedly unaffecte d relatives and has not been observed in isolation in an affected individual, ra ising the possibility that only modifies disease or may not be disease causing. Additional information is needed to fully assess the clinical significance of th e Tyr282His variant. |
| Invitae | RCV003517133 | SCV004285227 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2023-11-15 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 282 of the DSC2 protein (p.Tyr282His). This variant is present in population databases (rs397517405, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 46198). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DSC2 protein function with a positive predictive value of 80%. 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. |