ClinVar Miner

Submissions for variant NM_001927.4(DES):c.1216C>T (p.Arg406Trp) (rs121913003)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000056781 SCV000231642 pathogenic not provided 2016-04-28 criteria provided, single submitter clinical testing
GeneDx RCV000056781 SCV000235790 pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing The R406W variant in the DES gene has been published as a de novo variant in multiple patients with cardiac and skeletal myopathy (Dalakas et al., 2000; Park et al., 2000; Dagvadorj et al., 2004). In one study, each of four patients presented with early onset cardiac arrhythmia and conduction block followed by muscle weakness and progressive atrophy in the lower extremities (Dagvadorj et al., 2004). In addition, the R406W variant has been classified as a pathogenic variant by another clinical laboratory in ClinVar (SCV000231642.1; Landrum et al., 2016). The R406W variant, located in the C-terminal part of the desmin core domain, severely affected the ability of desmin to assemble into functional filaments (Park et al., 2000; Chourbagi et al., 2011). The Arginine 406 residue is highly conserved across species, and the R406W variant was not observed in over 300 control chromosomes (Park et al., 2000). Furthermore, the R406W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, R406W is interpreted to be a pathogenic variant.
Center for Genetic Medicine Research,Children's National Medical Center RCV000018320 SCV000265769 likely pathogenic Myofibrillar myopathy 1 2015-12-01 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000018320 SCV000271350 pathogenic Myofibrillar myopathy 1 2015-03-11 criteria provided, single submitter clinical testing The p.Arg406Trp variant in DES is absent from large populations sequenced by the Exome Aggregation Consortium ( but has been reported i n at least 5 individuals with clinical features of desminopathies, including con duction system disease +/-cardiomyopathy (DCM and RCM) and skeletal myopathy (sa me individuals reported in multiple papers; Dalakas 2000, Park 2000, Dagvadirj 2 004, Olive 2004, Wahbi 2012). In at least least 4 individuals the variant had oc curred de novo (paternity confirmed; same individuals reported in multiple paper s; Dalakas 2000, Park 2000, Dagvadirj 2004, Olive 2004). In vitro functional stu dies provide some evidence that the p.Arg406Trp variant impacts protein function (Park 2000, Chourbagi 2011). However, these types of assays sometimes do not ac curately represent biological function. In summary, this variant meets our crite ria to be classified as pathogenic for desminopathy with cardiac and skeletal my opathy involvement in an autosomal dominant manner ( onalizedmedicine/LMM) based upon absence from the general population and de novo occurrence.
Invitae RCV000627795 SCV000552187 pathogenic Myofibrillar myopathy 1; Muscular dystrophy, limb-girdle, type 2R 2020-02-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 406 of the DES protein (p.Arg406Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs121913003, ExAC no frequency). This variant has been shown to arise de novo in individuals affected with desmin myopathy (PMID: 10717012, 10905661, 14991347). Experimental studies have shown that this missense change disrupts salt-bridge formation and decreases the force generation capacity of mouse muscles when virally introduced (PMID: 21262226, 23425003). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018320 SCV000038599 pathogenic Myofibrillar myopathy 1 2000-06-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000056781 SCV000087894 not provided not provided no assertion provided not provided
Institute of Human Genetics, Klinikum rechts der Isar RCV000018320 SCV001149752 pathogenic Myofibrillar myopathy 1 2018-08-20 no assertion criteria provided clinical testing

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