ClinVar

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 39 of the HSPB1 protein (p.Pro39Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 22176143, 27816334, 28144995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 533814). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSPB1 protein function. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 25965061, 28595321). For these reasons, this variant has been classified as Pathogenic.