Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000685855 | SCV000813355 | uncertain significance | Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 | 2019-01-02 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine with alanine at codon 1373 of the DSP protein (p.Thr1373Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs200745877, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 21397041, 27532257). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. |
| Color | RCV000773962 | SCV000907662 | uncertain significance | Cardiomyopathy | 2018-09-16 | criteria provided, single submitter | clinical testing | Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the central rod domain of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a Finnish individual affected with arrhythmogenic right ventricular cardiomyopathy, two individuals with self-reported arrhythmia and one individual diagnosed with paroxysmal tachycardia (PMID: 21397041), as well as multiple asymptomatic individuals (PMID: 23651034). This variant has also been identified in 19/245796 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. |