7-76303816-C-T

Position:

• chr7-76303816-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001540.5(HSPB1):​c.379C>T​(p.Arg127Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.721

Genes affected

HSPB1 (HGNC:5246): (heat shock protein family B (small) member 1) This gene encodes a member of the small heat shock protein (HSP20) family of proteins. In response to environmental stress, the encoded protein translocates from the cytoplasm to the nucleus and functions as a molecular chaperone that promotes the correct folding of other proteins. This protein plays an important role in the differentiation of a wide variety of cell types. Expression of this gene is correlated with poor clinical outcome in multiple human cancers, and the encoded protein may promote cancer cell proliferation and metastasis, while protecting cancer cells from apoptosis. Mutations in this gene have been identified in human patients with Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a region_of_interest Interaction with TGFB1I1 (size 135) in uniprot entity HSPB1_HUMAN there are 28 pathogenic changes around while only 1 benign (97%) in NM_001540.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 7-76303816-C-T is Pathogenic according to our data. Variant chr7-76303816-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76303816-C-T is described in Lovd as [Pathogenic]. Variant chr7-76303816-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPB1	NM_001540.5	c.379C>T	p.Arg127Trp	missense_variant	2/3	ENST00000248553.7	NP_001531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7	c.379C>T	p.Arg127Trp	missense_variant	2/3	1	NM_001540.5	ENSP00000248553	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2F Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Aug 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2024	Published functional studies demonstrate a damaging effect: hyperphosphorylation and reduced anterograde transport of neurofilaments, disturbed microtubule dynamics, and defective autophagy (PMID: 30669930, 20178975, 22031878, 23728742); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23728742, 22031878, 20178975, 20660910, 21983720, 16215937, 21149811, 36539320, 36291591, 30669930, 34255403, 15122254, 32334137, 33509756, 34650302, 16087758, 28286897, 35297556) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 15, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2023	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. -

Neuronopathy, distal hereditary motor, type 2B Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 28, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	0.99	A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.85		Loss of disorder (P = 0.0191);
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		-5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs29001571; hg19: chr7-75933133;