ClinVar

Description

The HSPB1 c.116C>T (p.Pro39Leu) variant is a missense variant that has been reported in at least three studies, in which it was found in a heterozygous state in at least eight unrelated individuals with Charcot-Marie-Tooth disease type 2 or distal hereditary motor neuropathy (Capponi et al. 2011; Echaniz-Laguna et al. 2017; Tanabe et al. 2018). In several families, multiple affected individuals were heterozygous for the variant and in at least one individual, the variant was shown to be de novo. The p.Pro39Leu variant is reported at a frequency of 0.00001 in the European (non-Finnish) population from the Genome Aggregation Database (version 2.1.1), though this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Physicochemical studies of the p.Pro39Leu variant noted a decrease in phosphorylation-dependent dissociation of large oligomers and decreased chaperoning activity compared to wildtype (Muranova et al. 2015). Furthermore, the p.Pro39Leu variant was associated with mitochondrial dysfunction in motor neurons and increased vulnerability to oxidative stress (Kalmar et al. 2017). Based on the available evidence, the p.Pro39Leu variant is classified as pathogenic for HSPB1-related axonal neuropathies.