Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001888217 | SCV002140838 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2021-04-09 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with DSC2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with proline at codon 581 of the DSC2 protein (p.Thr581Pro). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and proline. |
All of Us Research Program, |
RCV004009252 | SCV004831879 | uncertain significance | Familial isolated arrhythmogenic right ventricular dysplasia | 2023-06-08 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with proline at codon 581 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). 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 1/251074 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. |