Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001851414 | SCV002147253 | uncertain significance | Duchenne muscular dystrophy | 2021-08-21 | criteria provided, single submitter | clinical testing | 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. Studies have shown that when in cis with the c.650-39575A>C variant, these variants are associated with altered splicing, which introduces a premature termination codon (PMID: 28495050). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in cis with the c.650-39575A>C variant in individual(s) with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 446469). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change falls in intron 7 of the DMD gene. It does not directly change the encoded amino acid sequence of the DMD protein. |
| Victorian Clinical Genetics Services, |
RCV001851414 | SCV003921858 | pathogenic | Duchenne muscular dystrophy | 2022-03-31 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 (MIM#310200), Becker muscular dystrophy (MIM#300376), and dilated cardiomyopathy 3B (DCM; MIM#302045). (I) 0109 - This gene is associated with X-linked recessive disease. This gene is primarily associated with X-linked recessive disease relating to the muscular dystrophy phenotypes, however it is also associated with X-linked dominant DCM (OMIM, PMID: 26066469). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Sequencing of cDNA created from mRNA from a hemizygous individual's muscle tissue, has demonstrated that this variant results in the formation of a cryptic pseudoexon. This insertion causes a shift in the reading frame (p.(Asp217Alafs*2)), and the formation of a protein predicted to undergo nonsense mediated decay (NMD), however some residual wildtype transcript did remain (PMID: 28495050). (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported as pathogenic, and observed in individuals with Duchenne muscular dystrophy (DMD; DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been observed in a hemizygous individual with milder DMD, and has been classified as likely pathogenic and pathogenic (ClinVar, LOVD, PMID: 28495050). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Institute of Human Genetics, |
RCV000515745 | SCV000611837 | likely pathogenic | Elevated circulating creatine kinase concentration | no assertion criteria provided | clinical testing |