Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000641080 | SCV000762698 | uncertain significance | Charcot-Marie-Tooth disease type 2F | 2018-11-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glutamine at codon 127 of the HSPB1 protein (p.Arg127Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HSPB1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Different missense substitutions at this codon (p.R127L, p.R127W) have been determined to be pathogenic (PMID: 26675522, 25025039, 23728742, 16215937, 22031878, 21983720, 15122254, 20178975). This suggests that the arginine residue is critical for HSPB1 protein function and that other missense substitutions at this position may also be pathogenic. 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. |