ClinVar Miner

Submissions for variant NM_004006.3(DMD):c.8333G>A (p.Arg2778His)

dbSNP: rs2071050854
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001235491 SCV001408180 uncertain significance Duchenne muscular dystrophy 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2778 of the DMD protein (p.Arg2778His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Becker muscular dystrophy (PMID: 26934379). ClinVar contains an entry for this variant (Variation ID: 961743). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001358700 SCV001554516 uncertain significance not specified 2022-07-22 criteria provided, single submitter clinical testing Variant summary: DMD c.8333G>A (p.Arg2778His) results in a non-conservative amino acid change located in the Central rod domain: Repeat 22 (DOVE database) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183412 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8333G>A has been reported in the literature in two affected male individuals from a family with features that resembled milder phenotypes of LGMD or BMD (Reddy_2016). One of these individuals who underwent WES had a positive staining for dystrophin on muscle biopsy and was able to father children. This report does not provide unequivocal conclusions about association of the variant with Dystrophinopathies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV001760246 SCV001988971 uncertain significance not provided 2019-10-21 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26934379)
Natera, Inc. RCV001828872 SCV002087684 uncertain significance Becker muscular dystrophy; Duchenne muscular dystrophy; Cardiomyopathy; Dystrophin deficiency 2020-06-05 no assertion criteria provided clinical testing

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