rs770272088

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM1PM2PP3_StrongPP5_Very_Strong

The NM_001540.5(HSPB1):c.250G>A(p.Gly84Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,392,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HSPB1
NM_001540.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 5.12

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:

HSPB1 (HGNC:):

HSPB1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS1

Transcript NM_001540.5 (HSPB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

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, 0.973

PP5

Variant 7-76302962-G-A is Pathogenic according to our data. Variant chr7-76302962-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 632006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76302962-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-76302962-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPB1	NM_001540.5 linkuse as main transcript	c.250G>A	p.Gly84Arg	missense_variant	1/3	ENST00000248553.7	NP_001531.1	P04792V9HW43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7 linkuse as main transcript	c.250G>A	p.Gly84Arg	missense_variant	1/3	1	NM_001540.5	ENSP00000248553.6		P04792

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1392122

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

687784

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.24e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2F

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 84 of the HSPB1 protein (p.Gly84Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant HSPB1-related conditions (PMID: 18344398, 18832141, 21892769, 25429913). This variant has been reported in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 28379183); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 632006). 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: 18344398, 23948568). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 11, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 26, 2022	This variant has been identified in at least one individual with clinical features associated with Charcot-Marie-Tooth disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant results in the same amino acid change as another variant (c.250G>C; p.Gly84Arg) considered to be pathogenic or likely pathogenic, strongly indicating this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was found to affect protein stability and decrease chaperone activity compared to wild-type resulting in abnormal cytoplasmic aggregation (PMID: 23948568, 31573509). -

HSPB1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 05, 2017

The HSPB1 c.250G>A (p.Gly84Arg) missense variant has been reported in two studies and found in a total of three affected individuals, including in a homozygous state in two siblings with distal hereditary motor neuropathy (dHMN) and in a presumed heterozygous state in one individual with Charcot-Marie-Tooth, type 2 (CMT2) (Manganelli et al. 2014; Ho et al. 2017). This variant was also identified in a heterozygous state in both presumably unaffected parents of the homozygous siblings. A second variant at the same nucleotide position, c.250G>C, also results in a p.Gly84Arg amino acid change and has been reported in a total of five individuals, including in a homozygous state in one individual with early onset CMT2, in a heterozygous state in two individuals with dHMN, and in a heterozygous state in the parents of the homozygous individual, both of whom displayed sub-clinical features, (James et al. 2008; Houlden et al. 2008; Fischer et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.000017 in the European (non-Finnish) population of the Genome Aggregation Database, but this is based on one allele in a region of good sequencing coverage so it is presumed to be rare. Expression of the p.Gly84Arg variant in HeLa cells led to abnormal protein aggregation (James et al. 2008), and protein interaction studies revealed that while the p.Gly84Arg variant does not affect neurofilament assembly, it does impact mobility and accessibility of the N-terminal domain, which modifies interdimer contacts in HspB1 oligomers (Nefedova et al. 2013; Nefedova et al. 2017). Based on the collective evidence, the c.250G>A (p.Gly84Arg) variant is classified as likely pathogenic for HSPB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

2.9

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Benign

0.063

Polyphen

1.0

Vest4

0.97

MutPred

0.81

Gain of solvent accessibility (P = 0.0128);

MVP

0.99

MPC

1.7

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.74

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