Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000559787 | SCV000657397 | uncertain significance | Bethlem myopathy 1 | 2018-08-17 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with proline at codon 2444 of the COL6A3 protein (p.Arg2444Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL6A3-related disease. This variant occurs with a pathogenic variant (p.Gln26*) in COL6A3 in an individual affected with muscular dystrophy (Invitae database). Family studies indicate that these two variants are on opposite chromosomes (in trans), which suggests the c.7331G>C substitution may contribute to disease. 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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance. |