ClinVar Miner

Submissions for variant NM_001927.4(DES):c.1285C>T (p.Arg429Ter) (rs150974575)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154519 SCV000204191 likely pathogenic Primary dilated cardiomyopathy; Myofibrillar myopathy 1; Neuromuscular disease 2013-06-12 criteria provided, single submitter clinical testing The Arg429X variant in DES has not been previously reported in individuals with isolated cardiomyopathy, but has been identified in 1/8600 European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e; dbSNP rs150974575). It has also been identified by ou r laboratory in 1 family, where it was present in trans with a second DES varian t (frameshift) in 2 individuals with features consistent with a desminopathy. Ea ch unaffected parent carried 1 of the variants, which is suggestive of recessive inheritance. This variant leads to a premature termination codon at position 42 9, which is predicted to lead to a truncated or absent protein. The spectrum of reported DES variants includes several similar variants (nonsense, splice, frame shift; Park 2000, Schroeder 2003, Dunand 2009, Hong 2011, Wahbi 2011). While one of these variants (Dunand 2009) showed clear autosomal dominant inheritance, th is could not be conclusively established for the other variants. In summary, thi s variant is likely to cause disease when present with a second DES variant, but additional studies are needed to fully establish its clinical significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000327525 SCV000344024 pathogenic not provided 2016-08-04 criteria provided, single submitter clinical testing
Invitae RCV001059931 SCV001224586 pathogenic Myofibrillar myopathy 1; Muscular dystrophy, limb-girdle, type 2R 2020-07-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg429*) in the DES gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs150974575, ExAC 0.01%). This variant has been observed in individuals affected with autosomal recessive DES-related conditions (PMID: 23815709, 25590979). ClinVar contains an entry for this variant (Variation ID: 177872). Loss-of-function variants in DES are known to be pathogenic (PMID: 23575897). For these reasons, this variant has been classified as Pathogenic.

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