Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000641078 | SCV000762696 | pathogenic | Charcot-Marie-Tooth disease axonal type 2F | 2019-09-12 | criteria provided, single submitter | clinical testing | This variant has been reported in individuals affected with distal hereditary motor neuropathy and Charcot-Marie-Tooth disease (PMID: 27816334, 23963299, Invitae) and has been reported to segregate with Charcot-Marie-Tooth disease in a single family (PMID: 23963299). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with tyrosine at codon 135 of the HSPB1 protein (p.Ser135Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Ser135Phe) has been determined to be pathogenic (PMID: 15122254, 18832141, 17881652). This suggests that the serine residue is critical for HSPB1 protein function and that other missense substitutions at this position may also be pathogenic. |
| Institute of Medical Genetics and Applied Genomics, |
RCV001268034 | SCV001446627 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Inherited Neuropathy Consortium | RCV000789965 | SCV000929351 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |