Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000464384 | SCV000550313 | uncertain significance | Duchenne muscular dystrophy | 2024-08-29 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2609 of the DMD protein (p.Gly2609Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 409927). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DMD protein function with a negative predictive value of 95%. 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. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786298 | SCV000925061 | uncertain significance | not provided | 2017-04-06 | no assertion criteria provided | provider interpretation | p.Gly2609Asp (c.7826G>A) in exon 53 of the DMD gene (NM_004006.2) Chromosome position X:31697538 C / T Given the lack of case data, and this variant's absence in the broader population, we classify it as being of unknown significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in family members. The DMD gene is associated with X-linked Duchenne Muscular Dystrophy (DMD) (MedGen UID:3925), Becker Muscular Dystrophy (BMD) (MedGen UID: 182959) and dilated cardiomyopathy (DCM) (MedGen UID: 472068). This is a completely novel variant. It has not been reported in the literature in association with disease, and it not present in population databases. Invitae reports that this variant is possibly mosaic in our patient, who has early-onset atrial fibrillation. It had not been reported to ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) by any lab as of 4/4/2017. This is a nonconservative amino acid change that replaces a nonpolar glycine with a negatively-charged aspartic acid. The glycine residue is not conserved across vertebrate species, and is frequently replaced with another nonpolar amino acid such as alanine or isoleucine. Of note, the default amino acid is aspartic acid in brush-tailed rat. No missense variants within 10 amino acids to either side are currently listed in ClinVar as Likely Pathogenic or Pathogenic. According to the Invitae report, 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 tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. There is good sequencing coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. |