Submissions for variant NM_001540.5(HSPB1):c.379C>T (p.Arg127Trp)

dbSNP: rs29001571

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489743	SCV000577216	pathogenic	not provided	2017-04-07	criteria provided, single submitter	clinical testing	The R127W pathogenic variant in the HSPB1 gene has been reported multiple times previously in association with HSPB1-related disorders (Evgrafov et al., 2004; Tang et al., 2005; Benedetti et al., 2010). Funcational studies suggest the R127W variant impacts protein function (Almeida-Souza et al., 2010; Almeida-Souza et al., 2011; Holmgren et al., 2013). The R127W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R127W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.
Athena Diagnostics Inc	RCV000489743	SCV000613674	pathogenic	not provided	2022-12-15	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to segregate with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 30669930, 29330367, 29048431).
Invitae	RCV000007907	SCV001582548	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 127 of the HSPB1 protein (p.Arg127Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease and/or distal hereditary motor neuropathy (PMID: 15122254, 16215937, 20660910). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7479). 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: 20178975, 22031878). This variant disrupts the p.Arg127 amino acid residue in HSPB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25025039, 26675522). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007907	SCV001934256	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2020-10-20	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007906	SCV001950127	pathogenic	Neuronopathy, distal hereditary motor, type 2B	2021-07-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354152	SCV002620136	pathogenic	Inborn genetic diseases	2021-07-19	criteria provided, single submitter	clinical testing	The p.R127W pathogenic mutation (also known as c.379C>T), located in coding exon 2 of the HSPB1 gene, results from a C to T substitution at nucleotide position 379. The arginine at codon 127 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been observed in the heterozygous state in several individuals with Charcot-Marie-Tooth disease, axonal, type 2F (CMT2F) and distal hereditary motor neuronopathy type IIB (dHMNIIB), and it has been shown to segregate with Charcot-Marie-Tooth disease type 2 in multiple unrelated families (Evgrafov OV et al. Nat Genet, 2004 Jun;36:602-6; Chen J et al. Nan Fang Yi Ke Da Xue Xue Bao, 2021 Jan;41:75-78; Katz M et al. J Neurol Sci, 2020 06;413:116809; Tanabe H et al. J Peripher Nerv Syst, 2018 03;23:40-48; Tang B et al. Arch Neurol, 2005 Aug;62:1201-7; Solla P et al. J Neurol Neurosurg Psychiatry, 2010 Sep;81:958-62; Echaniz-Laguna A et al. Hum Mutat, 2017 05;38:556-568). In vitro experimental studies show that this alteration affects neurofilament interaction with kinesin, destabilizes intersubunit contacts, and may induce HspB1 monomerization (Almeida-Souza L et al. J Biol Chem, 2010 Apr;285:12778-86; Almeida-Souza L et al. J Neurosci, 2011 Oct;31:15320-8; Holmgren A et al. Acta Neuropathol, 2013 Jul;126:93-108). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000007907	SCV004031065	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2023-08-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000489743	SCV004564308	pathogenic	not provided	2023-01-06	criteria provided, single submitter	clinical testing	The HSBP1 c.379C>T; p.Arg127Trp variant (rs29001571) is reported in the literature in numerous individuals affected with CMT type 2 and distal hereditary motor neuropathy including a single de novo occurrence (Evgrafov 2004, Katz 2020, Solla 2010, Wu 2022). This variant was also found to segregate with disease in multiple families (Evgrafov 2004, Solla 2010). Functional analyses found the variant protein disrupts microtubule dynamics and reduces anterograde transport of neurofilaments (Almedia-Souza 2011, Holmgren 2013). This variant is also reported in ClinVar (Variation ID: 7479) and absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 127 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.774). Based on available information, this variant is considered to be pathogenic. References: Almeida-Souza L et al. Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy. J Neurosci. 2011 Oct 26;31(43):15320-8. PMID: 22031878. Evgrafov OV et al. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet. 2004 Jun;36(6):602-6. PMID: 15122254. Holmgren A et al. Charcot-Marie-Tooth causing HSPB1 mutations increase Cdk5-mediated phosphorylation of neurofilaments. Acta Neuropathol. 2013 Jul;126(1):93-108. PMID: 23728742. Katz M et al. Mutations in heat shock protein beta-1 (HSPB1) are associated with a range of clinical phenotypes related to different patterns of motor neuron dysfunction: A case series. J Neurol Sci. 2020 Jun 15;413:116809. PMID: 32334137. Solla P et al. Heat shock protein 27 R127W mutation: evidence of a continuum between axonal Charcot-Marie-Tooth and distal hereditary motor neuropathy. J Neurol Neurosurg Psychiatry. 2010 Sep;81(9):958-62. PMID: 20660910. Wu C et al. Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy. Ann Clin Transl Neurol. 2022 May;9(5):633-643. PMID: 35297556.
OMIM	RCV000007906	SCV000028111	pathogenic	Neuronopathy, distal hereditary motor, type 2B	2005-08-01	no assertion criteria provided	literature only
OMIM	RCV000007907	SCV000028112	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2005-08-01	no assertion criteria provided	literature only