7-76302828-C-T

Position:

chr7-76302828-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong

The NM_001540.5(HSPB1):c.116C>T(p.Pro39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 1,453,104 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

HSPB1
NM_001540.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 1.58

Variant links:

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]

HSPB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a chain Heat shock protein beta-1 (size 204) in uniprot entity HSPB1_HUMAN there are 63 pathogenic changes around while only 11 benign (85%) in NM_001540.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-76302828-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2884503.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 7-76302828-C-T is Pathogenic according to our data. Variant chr7-76302828-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 533814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76302828-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-76302828-C-T is described in Lovd as [Pathogenic]. Variant chr7-76302828-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB1	NM_001540.5 linkuse as main transcript	c.116C>T	p.Pro39Leu	missense_variant	1/3	ENST00000248553.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB1	ENST00000248553.7 linkuse as main transcript	c.116C>T	p.Pro39Leu	missense_variant	1/3	1	NM_001540.5	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000441

AC:

AN:

226832

Hom.:

AF XY:

0.00

AC XY:

AN XY:

125734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000986

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000895

AC:

AN:

1453104

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

722802

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000991

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000841

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 18, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 09, 2021	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). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	HSPB1: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting -

Charcot-Marie-Tooth disease

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -

HSPB1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 29, 2024

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. 2018. PubMed ID: 29381233; Muranova et al 2015. PubMed ID: 25965061; and Kalmar et al 2017. PubMed ID: 28595321). This variant is reported in 0.00099% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Charcot-Marie-Tooth disease axonal type 2F

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

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. -

Neuronopathy, distal hereditary motor, type 2B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 24, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3. -

HSPB1-related axonal neuropathies

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 16, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.65

MetaRNN

Uncertain

0.61

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.1

REVEL

Benign

0.20

Sift

Benign

0.79

Sift4G

Benign

0.31

Polyphen

0.0070

Vest4

0.70

MutPred

0.47

Loss of disorder (P = 0.0539);

MVP

0.94

MPC

0.58

ClinPred

0.18

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.38

gMVP

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over