ClinVar Miner

Submissions for variant NM_004006.2(DMD):c.5530C>T (p.Arg1844Ter) (rs1064325)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080659 SCV000112561 pathogenic not provided 2016-11-28 criteria provided, single submitter clinical testing
Invitae RCV000178001 SCV000550264 pathogenic Duchenne muscular dystrophy 2016-04-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1844 (p.Arg1844*) of the DMD gene. It is expected to result in an absent or disrupted protein product. Truncating variants in DMD are known to be pathogenic (PMID: 16770791). This particular variant has been reported in multiple individuals with Duchenne muscular dystrophy (PMID: 21396098, 23536893) and has also been shown to have arisen de novo in an additional individual with Duchenne muscular dystrophy (PMID: 14695533). For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000080659 SCV000925055 pathogenic not provided 2016-07-11 no assertion criteria provided provider interpretation p.Arg1844* (c.5530C>T) in exon 39 of the DMD gene (NM_004006.2) Seen in our center in an adult male with dilated cardiomyopathy, without muscular dystrophy. Genetic testing consistent with mosaicism. Given the case data, type of variant, and rarity, we consider this variant very likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). It is well established that nonsense variants in DMD are pathogenic (Juan-Mateu et al 2015). Loss of function variants like this cause nearly all cases of Duchenne muscular dystrophy. Consistent with this, there are only 12 loss of function variants in DMD in the ExAC database. This is in contrast to the number of loss of function variants expected for the gene's size, 114. Thus, there is strong evidence that nonsense DMD variants are pathogenic. DMD variants have also been implicated in isolated dilated cardiomyopathy, without muscular dystrophy. Jeff Towbin's group reported combined LOD score of 4.33 across two kindreds with x-linked DCM and then later identified a missense variant in DMD in one of these kindreds. See Nakamura et al (2015) for recent review of DCM associated with DMD variants (Pharmaceuticals 2015, 8, 303-320; doi:10.3390/ph8020303). Per that review, most reported cases of DCM with DMD variants have had an early onset (teens) and progressive course. Nakamura notes that while some cases have overt and progressive heart failure others have a very mild DCM that is responsive to beta blockers and ACE inhibitors. Female carriers with more slowly progressive DCM in mid-life have been reported. Multiple cases have been reported with DCM and DMD variants with normal skeletal muscle dystrophin on western blotting and other histopathological analysis. Per the lab report: "This particular variant has been reported in multiple individuals with Duchenne muscular dystrophy (PMID: 21396098, 23536893) and has also been shown to have arisen de novo in an additional individual with Duchenne muscular dystrophy (PMID: 14695533)." In total the variant has not been seen in ~60,000 individuals from publicly available population datasets. There is no variation at codon 1844 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 11th, 2016). The average coverage at that site in ExAC is 40x.

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