Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000056785 | SCV000235799 | uncertain significance | not provided | 2020-12-31 | criteria provided, single submitter | clinical testing | Reported in a patient with a history of limb weakness, respiratory dysfunction, spine ankylosis, and a myogenic pattern observed on electromyogram, however, a normal electrocardiogram and echocardiogram were also reported and no segregation studies were described (Hong et al., 2011); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Expression studies in both mouse and human cell lines suggest that T445A causes abnormal desmin organization in the cytoplasm (Hong et al., 2011); however, additional studies are needed to validate the functional effect of this variant; This variant is associated with the following publications: (PMID: 20696008, 29926427) |
| Invitae | RCV001854165 | SCV002215136 | uncertain significance | Desmin-related myofibrillar myopathy | 2023-08-23 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 445 of the DES protein (p.Thr445Ala). This missense change has been observed in individual(s) with desminopathy and/or dilated cardiomyopathy (PMID: 20696008, 32880476). This variant is present in population databases (rs267607498, gnomAD 0.007%). ClinVar contains an entry for this variant (Variation ID: 66399). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DES function (PMID: 20696008). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DES protein function. |
| Fulgent Genetics, |
RCV002483084 | SCV002789127 | uncertain significance | Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type | 2021-11-09 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003162434 | SCV003878355 | uncertain significance | Cardiovascular phenotype | 2022-11-28 | criteria provided, single submitter | clinical testing | The p.T445A variant (also known as c.1333A>G), located in coding exon 8 of the DES gene, results from an A to G substitution at nucleotide position 1333. The threonine at codon 445 is replaced by alanine, an amino acid with similar properties. This variant has been detected in an individual with skeletal myopathy; however, only one gene was analyzed. The same study reported this variant to result in abnormal desmin aggregates in cell lines (Hong D et al. Neuropathol. Appl. Neurobiol., 2011 Apr;37:257-70). Additionally, this alteration was reported in a dilated cardiomyopathy cohort; however, clinical details were limited (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). 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. |
| Epithelial Biology; Institute of Medical Biology, |
RCV000056785 | SCV000087898 | not provided | not provided | no assertion provided | not provided |