Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000201114 | SCV000255712 | pathogenic | Duchenne muscular dystrophy | 2012-09-12 | criteria provided, single submitter | clinical testing | |
| Eurofins Ntd Llc |
RCV000727448 | SCV000708596 | pathogenic | not provided | 2017-05-16 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001293467 | SCV001482039 | pathogenic | Qualitative or quantitative defects of dystrophin | 2021-02-22 | criteria provided, single submitter | clinical testing | Variant summary: DMD c.2623-3C>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 acceptor site and creates a new cryptic intronic one. Experimental evidence supports these predictions demonstrating the variant leads to the retention of the last 2 AG nucleotides of intron 20 in the mature dystrophin mRNA (Sedlackova_2009, Adkin_2012). The variant was absent in 183222 control chromosomes (gnomAD). c.2623-3C>G has been reported in the literature in individuals affected with Dystrophinopathies (e.g. Sedlackova_2009, Adkin_2012). These data indicate that the variant may be associated with disease. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Victorian Clinical Genetics Services, |
RCV000201114 | SCV005398900 | likely pathogenic | Duchenne muscular dystrophy | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Duchenne muscular dystrophy (DMD; MIM#310200), Becker muscular dystrophy (BMD; MIM#300376) and X-linked dominant dilated cardiomyopathy, 3B (DCM; MIM#302045). (I) 0108 - This gene is associated with both recessive and dominant disease. DMD and BMD are both associated with X-linked recessive disease, while females who are heterozygous for a pathogenic DMD variant are at increased risk for DCM. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). This variant has been reported to result in the retention of the last two nucleotides in intron 20 and create a new acceptor splice site; however, no specific functional studies have been shown (PMIDs: 19783145, 22182525). (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same non-canonical splice site, is present in gnomAD (v2) at a frequency of 0.0000055 (1 heterozygote, 0 homozygotes). (SB) 0508 - In silico predictions for abnormal splicing are inconclusive. (I) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported at least five individuals with Duchenne muscular dystrophy and/or dystrophinopathies (ClinVar; PMIDs: 19783145, 22182525). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Using patient fibroblasts and RNA extracted from patient muscle tissue, this variant has been reported to retain the last two nucleotides in intron 20 and create a new splice site, however specific functional studies demonstrating this has not been shown ((PMIDs: 19783145, 22182525). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |