Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000056786 | SCV000335262 | likely pathogenic | not provided | 2015-09-11 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000056786 | SCV001502389 | pathogenic | not provided | 2022-12-01 | criteria provided, single submitter | clinical testing | DES: PP1:Strong, PM2, PS4:Moderate, PP3, PP4, PS3:Supporting |
| Labcorp Genetics |
RCV001854166 | SCV002238968 | pathogenic | Desmin-related myofibrillar myopathy | 2022-07-29 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DES function (PMID: 17221859). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 66400). This missense change has been observed in individuals with clinical features of autosomal dominant desminopathy (PMID: 14711882, 23051780, 29892087). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 449 of the DES protein (p.Lys449Thr). |
| Athena Diagnostics | RCV000056786 | SCV002770669 | likely pathogenic | not provided | 2021-06-22 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family with myofibrillar myopathy (PMID: 23051780) and one family with dilated cardiomyopathy (PMID: 29892087). Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Though studies suggest that this variant impacts filament-formation in some in vitro experiments, additional research is needed to understand how this relates to disease in vivo (PMID: 17221859). Additionally, though patient-derived samples have shown abnormal desmin aggregates, it is possible that results could be influenced by factors other than this variant (PMID: 23051780). Computational tools predict that this variant is damaging. |
| Victorian Clinical Genetics Services, |
RCV001854166 | SCV005398106 | pathogenic | Desmin-related myofibrillar myopathy | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with dilated cardiomyopathy 1I (MIM#604765), myofibrillar myopathy 1 (MIM#601419) and Kaeser type neurogenic scapuloperoneal syndrome (MIM#181400). (I) 0108 - This gene is associated with both recessive and dominant disease. The majority of disease-associated DES variants exhibit autosomal dominant inheritance, with rare cases of biallelic truncating and missense variants reported for myopathy (PMID: 29926427). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in association with myofibrillar myopathy (PMIDs: 23051780, 29926427) and dilated cardiomyopathy (PMID: 29892087). In addition, it is regarded likely pathogenic and pathogenic in ClinVar by diagnostic laboratories. (SP) 0901 - This variant has strong evidence for segregation with disease. It was shown to segregate with myofibrillar myopathy in a multi-generational Irish family (PMID: 23051780). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Epithelial Biology; Institute of Medical Biology, |
RCV000056786 | SCV000087899 | not provided | not provided | no assertion provided | not provided | ||
| Wellcome Centre for Mitochondrial Research, |
RCV000239724 | SCV000298020 | pathogenic | Myofibrillar myopathy | 2016-08-16 | no assertion criteria provided | clinical testing |