Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000802498 | SCV000942332 | uncertain significance | Desmin-related myofibrillar myopathy | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 402 of the DES protein (p.Ile402Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of DES-related conditions (PMID: 33373648; Invitae). ClinVar contains an entry for this variant (Variation ID: 201708). 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 DES protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DES function (PMID: 33373648). This variant disrupts the p.Ile402 amino acid residue in DES. Other variant(s) that disrupt this residue have been observed in individuals with DES-related conditions (PMID: 25557463), which suggests that this may be a clinically significant amino acid residue. 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. |
| Ambry Genetics | RCV002345640 | SCV002654192 | uncertain significance | Cardiovascular phenotype | 2021-09-24 | criteria provided, single submitter | clinical testing | The p.I402T variant (also known as c.1205T>C), located in coding exon 6 of the DES gene, results from a T to C substitution at nucleotide position 1205. The isoleucine at codon 402 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a subject with dilated cardiomyopathy and a family history of sudden cardiac death; the authors also suggested this alteration may have an impact on protein function (Fischer B et al. Int J Cardiol, 2021 04;329:167-174). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |