Submissions for variant NM_004006.3(DMD):c.187-10_187-6del

dbSNP: rs1557079581

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548502	SCV000625854	uncertain significance	Duchenne muscular dystrophy	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the DMD gene. It does not directly change the encoded amino acid sequence of the DMD protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with DMD-related muscular dystrophy (PMID: 26911353). ClinVar contains an entry for this variant (Variation ID: 455872). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV001755794	SCV001987986	uncertain significance	not provided	2020-09-30	criteria provided, single submitter	clinical testing	Reported in a patient referred for Duchenne or Becker muscular dystrophy genetic testing (Okubo et al., 2016); however, additional clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 455872; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26911353)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844189	SCV002103720	uncertain significance	not specified	2022-02-23	criteria provided, single submitter	clinical testing	Variant summary: DMD c.187-10_187-6delTTGTT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict a potential impact on normal splicing: two predict the variant has no significant impact on splicing, while two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 183193 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.187-10_187-6delTTGTT has been reported in the literature in an individual affected with Duchenne- or Becker muscular dystrophy without evidence for causality (Okubo_2016). 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001829540	SCV002092929	uncertain significance	Becker muscular dystrophy; Duchenne muscular dystrophy; Cardiomyopathy; Dystrophin deficiency	2020-01-13	no assertion criteria provided	clinical testing