Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000641079 | SCV000762697 | pathogenic | Charcot-Marie-Tooth disease type 2F | 2018-09-24 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with leucine at codon 39 of the HSPB1 protein (p.Pro39Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to segregate with autosomal dominant Charcot Marie Tooth disease in several families (PMID: 28144995, 27816334, 18832141, 22176143). This variant has also been reported in several other individuals affected with Charcot Marie Tooth disease including at least one individual in whom the variant appeared to arise de novo (PMID: 28144995, 29381233). ClinVar contains an entry for this variant (Variation ID: 533814). Experimental studies have shown that this missense change causes mitochondrial dysfunction, increased aggregation, increased resistance to dissociation, and decreased chaperone-like activity of HSPB1 (PMID: 25965061, 28595321). For these reasons, this variant has been classified as Pathogenic. |
| Inherited Neuropathy Consortium | RCV000789058 | SCV000928407 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |