Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181320 | SCV000233614 | uncertain significance | not specified | 2016-09-29 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the DSP gene. The R1392Q variant has been previously reported in a 25 year old male diagnosed with idiopathic DCM who underwent a heart transplant; however, no informative segregation data were available (Marston et al., 2015). The R1392Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, the R1392Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, while this substitution occurs at a position that is conserved in mammals, Glutamine is tolerated at this position in at least one mammalian species. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. |
| Invitae | RCV000815172 | SCV000955619 | uncertain significance | Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 | 2018-12-07 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glutamine at codon 1392 of the DSP protein (p.Arg1392Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs201736018, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 26406308). ClinVar contains an entry for this variant (Variation ID: 199883). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; 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. |