Submissions for variant NM_001540.5(HSPB1):c.116C>T (p.Pro39Leu)

dbSNP: rs557327165

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641079	SCV000762697	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2025-01-17	criteria provided, single submitter	clinical testing	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). Invitae Evidence 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 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.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000789058	SCV001337299	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197515	SCV001368291	pathogenic	Neuronopathy, distal hereditary motor, type 2B	2019-01-24	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3.
Illumina Laboratory Services, Illumina	RCV001796974	SCV002038568	pathogenic	HSPB1-related axonal neuropathies	2021-06-16	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV002060745	SCV002497523	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	HSPB1: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting
Athena Diagnostics	RCV002060745	SCV002770664	pathogenic	not provided	2021-09-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant appears to occur de novo in one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Expression of this variant in a motor neuron cell line resulted in impaired mitochondrial function and transport (PMID: 28592321).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002060745	SCV003800118	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing	The HSBP1 c.116C>T; p.Pro39Leu variant (rs557327165) is reported in the literature in multiple individuals and families affected with Charcot-Marie-Tooth disease type 2 and distal hereditary motor neuropathy (Capponi 2011, Echaniz-Laguna 2017, Kalmar 2017, Rossor 2017). Functional analyses of the variant protein show increased protein aggregation, increased resistance to dissociation, reduced chaperone-like activity (Muranova 2015) and mitochondrial dysfunction (Kalmer 2017). This variant is reported in ClinVar (Variation ID: 533814) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Capponi S et al. HSPB1 and HSPB8 in inherited neuropathies: study of an Italian cohort of dHMN and CMT2 patients. J Peripher Nerv Syst. 2011 Dec;16(4):287-94. PMID: 22176143. Echaniz-Laguna A et al. Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations. Hum Mutat. 2017 May;38(5):556-568. PMID: 28144995. Kalmar B et al. Mitochondrial deficits and abnormal mitochondrial retrograde axonal transport play a role in the pathogenesis of mutant Hsp27-induced Charcot Marie Tooth Disease. Hum Mol Genet. 2017 Sep 1;26(17):3313-3326. PMID: 28595321. Muranova et al. Characterization of Mutants of Human Small Heat Shock Protein HspB1 Carrying Replacements in the N-Terminal Domain and Associated with Hereditary Motor Neuron Diseases. PLoS One. 2015 May 12;10(5):e0126248. PMID: 25965061. Rossor AM et al. Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene. Neuromuscul Disord. 2017 Jan;27(1):50-56. PMID: 27816334.
Inherited Neuropathy Consortium	RCV000789058	SCV000928407	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004544855	SCV004764438	pathogenic	HSPB1-related disorder	2024-03-05	no assertion criteria provided	clinical testing	The HSPB1 c.116C>T variant is predicted to result in the amino acid substitution p.Pro39Leu. This variant was reported in individuals with autosomal dominant Charcot-Marie-Tooth disease, type 2 (Houlden et al 2008. PubMed ID: 18832141; Volodarsky et al 2020. PubMed ID: 32376792; Tanabe et al. 2018. PubMed ID: 29381233). Functional studies suggest that the p.Pro39Leu variant led to abnormal mitochondrial axonal transport and abnormal phosphorylation (Kalmar et al 2017. PubMed ID: 28595321; Muranova et al 2015. PubMed ID: 25965061). This variant is reported in 0.00099% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.