ClinVar Miner

Submissions for variant NM_001927.4(DES):c.1360C>T (p.Arg454Trp) (rs267607490)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844627 SCV000204710 likely pathogenic Primary dilated cardiomyopathy; Neuromuscular disease 2012-05-24 criteria provided, single submitter clinical testing The Arg454Trp variant in DES has been identified in 1 individual with HCM and mu scle weakness and in 2 siblings with AV Block and cardiac hypertrophy that progr essed to heart failure (Bar 2007, Otten 2010). This variant was also absent from 600 chromosomes and reportedly occurred de novo in the individual with HCM (Bar 2007). Functional studies demonstrated an effect on filament formation (Bar 200 7, Levin 2010). Arginine (Arg) at position 454 is highly conserved in evolution and computational analyses (PolyPhen2 and SIFT) suggest that this variant may im pact the protein, though this information is not predictive enough to determine a pathogenic role. Desmin variants have been described in patients with cardiomy opathy +/- myopathy (desminopathies; Goldfarb 2009, van Spaendonck-Zwarts 2010). In summary, this data supports that the Arg454Trp variant is likely pathogenic, though is needed to fully establish its pathogenicity.
Center for Genetic Medicine Research,Children's National Medical Center RCV000211712 SCV000265762 likely pathogenic Myofibrillar myopathy 1 2015-12-01 criteria provided, single submitter research
GeneDx RCV000056789 SCV000321547 pathogenic not provided 2018-07-09 criteria provided, single submitter clinical testing The R454W pathogenic variant in the DES gene has been reported in one individual with severe hypertrophic cardiomyopathy (HCM) and skeletal myopathy who also harbored a pathogenic variant in the MYOT (LGMD-1A) gene (Bar et al., 2007). A muscle biopsy revealed abnormal desmin reactive deposits within the individual myofibers and ultrastructural analysis revealed granular electron-dense material (Bar et al., 2007). R454W has also been reported in two siblings who died in their late twenties after a history of atrioventricular block (AVB), pacemaker implantation, and severe biventricular cardiomyopathy (Otten et al., 2010). The family history was remarkable for AVB and cardiomyopathy in their deceased father, and genetic testing of their unaffected mother was negative for the R454W variant (Otten et al., 2010). Immunohistochemistry on myocardial samples showed severely disrupted desmin protein distribution and a marked decrease in connexin-43, desmoplakin, and PKP2 signals at the intercalated discs (Otten et al., 2010). Additional functional studies have suggested that R454W may lead to intermediate filament instability and also interfere with assembly at the level of dimer to tetramer association (Bar et al., 2007; Levin et al., 2010).The R454W variant has been observed de novo with and without confirmed parentage in multiple patients previously tested at GeneDx and in the published literature (Bar et al., 2007; Ackerman et al., 2016). Lastly, the variant is not observed in large population cohorts (Lek et al., 2016).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000056789 SCV000339496 pathogenic not provided 2017-11-24 criteria provided, single submitter clinical testing
Invitae RCV000684771 SCV000552172 pathogenic Myofibrillar myopathy 1; Muscular dystrophy, limb-girdle, type 2R 2020-04-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 454 of the DES protein (p.Arg454Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs267607490, ExAC no frequency). This variant has been reported to segregate with arrhythmogenic right ventricular cardiomyopathy (ARVC) in two families (PMID: 20423733, 25557463), has been reported in an individual with dilated cardiomyopathy (PMID:23349452) and in multiple unrelated individuals with myofibrillar myopathy (PMID: 22106715, 22153487, 27854218), and has been shown to arise de novo in an individual affected with progressive cardiac and skeletal myopathy (PMID: 17221859). ClinVar contains an entry for this variant (Variation ID: 66402). Experimental studies have suggested that this variant disrupts filament formation (PMID: 17221859, 20171226, 20448486). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics,University of Leuven RCV000498999 SCV000579529 pathogenic Primary dilated cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score pathogenic
Athena Diagnostics Inc RCV000056789 SCV000613086 likely pathogenic not provided 2016-07-19 criteria provided, single submitter clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore RCV000056789 SCV000087902 not provided not provided no assertion provided not provided
Blueprint Genetics RCV000155027 SCV000206888 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-10-07 no assertion criteria provided clinical testing

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