ClinVar Miner

Submissions for variant NM_001927.4(DES):c.1237G>A (p.Glu413Lys) (rs61726467)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000056782 SCV000235791 pathogenic not provided 2017-11-27 criteria provided, single submitter clinical testing The E413K variant has been reported to segregate with restrictive cardiomyopathy (RCM) in three members of one family (Pruszcyk et al., 2007). This variant has also segregated with RCM in multiple relatives of a family tested at GeneDx, and segregated with dilated cardiomyopathy in an unrelated family tested at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016). The E413K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies demonstrated that E413K caused defects in filament formation and indicated that the cellular filamentous networking properties were impaired, and showed that dot-like aggregates were accumulated throughout the cytoplasm of muscle fibers (Pruszczyk et al., 2007; Bar et al., 2007; Levin et al., 2010; Chourbagi et al., 2011).
Invitae RCV000685786 SCV000813283 likely pathogenic Myofibrillar myopathy 1; Muscular dystrophy, limb-girdle, type 2R 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 413 of the DES protein (p.Glu413Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with restrictive cardiomyopathy and atrioventricular conduction block in a single family. Histopathological analysis of one of the affected individuals revealed signs of myofibrillar myopathy (PMID: 16890305). This variant has also been been found in an individual affected with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 66398). Experimental studies have shown that this missense change induces desmin network disorganization, desmin aggregate formation and alters skeletal muscle force generation (PMID: 16890305, 17221859, 20448486, 21262226, 23425003 , 26789769). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000056782 SCV000087895 not provided not provided no assertion provided not provided

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