7-76302962-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1PM1PP3_StrongPP5_Very_Strong

The NM_001540.5(HSPB1):c.250G>C(p.Gly84Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000214 in 1,544,310 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 the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

HSPB1
NM_001540.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U: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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 7-76302962-G-C is Pathogenic according to our data. Variant chr7-76302962-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 220419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76302962-G-C is described in Lovd as [Likely_pathogenic]. Variant chr7-76302962-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB1	NM_001540.5 link	c.250G>C	p.Gly84Arg	missense_variant	Exon 1 of 3	ENST00000248553.7	NP_001531.1	P04792V9HW43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7 link	c.250G>C	p.Gly84Arg	missense_variant	Exon 1 of 3	1	NM_001540.5	ENSP00000248553.6		P04792

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000678

AC:

AN:

147494

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

80776

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:

0.0000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000230

AC:

AN:

1392122

Hom.:

Cov.:

AF XY:

0.0000204

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000286

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Mar 12, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease, and data include affected and unaffected individuals from multiple families. -

Oct 04, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PS1, PS3, PS4_moderate -

Jan 12, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a homozygous state in a patient with severe Charcot Marie Tooth disease whose heterozygous parents were more mildly affected with impaired tendon reflexes (PMID: 21892769); Published functional studies demonstrate a damaging effect on protein stability and ability to form large heterooligomers (PMID: 23948568), as well as enhanced cytoplasmic aggregation of the mutant protein (PMID: 18344398); Reported in patients with distal hereditary motor neuropathy in published literature (PMID: 18832141, 18344398, 27816334); 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: 32528171, 28000086, 32334137, 28797631, 18344398, 34128983, 27816334, 31573509, 18832141, 21892769, 23948568) -

Charcot-Marie-Tooth disease

Pathogenic:1Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Sep 03, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G84R variant (also known as c.250G>C), located in coding exon 1 of the HSPB1 gene, results from a G to C substitution at nucleotide position 250. The glycine at codon 84 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple patients with neuropathy in both heterozygous and homozygous states and has been functionally studied and shown to result in a defective protein. (Houlden H et al. Neurology, 2008 Nov;71:1660-8; James PA et al. J. Neurol. Neurosurg. Psychiatry, 2008 Apr;79:461-3; Fischer C et al. J. Neurol., 2012 Mar;259:515-23; Nefedova VV et al. Arch. Biochem. Biophys., 2013 Oct;538:16-24; Manganelli F et al. J. Peripher. Nerv. Syst., 2014 Dec;19:292-8; Ho CC et al. Int J Mol Sci, 2017 Apr;18:(4). pii: E770). The same amino acid change has been reported in the literature resulting from a different nucleotide substitution, c.250G>A (Manganelli F et al. J. Peripher. Nerv. Syst., 2014 Dec;19:292-8; Ho CC et al. Int J Mol Sci, 2017 Apr;18:(4). pii: E770). Based on data from gnomAD, the C allele has an overall frequency of approximately 0.0007% (1/147494). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Charcot-Marie-Tooth disease axonal type 2F

Pathogenic:1

May 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease or distal hereditary motor neuropathy (dHMN) (PMID: 18344398, 18832141, 21892769, 25429913). ClinVar contains an entry for this variant (Variation ID: 220419). 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. -

Distal hereditary motor neuropathy type 2

Pathogenic:1

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in HSPB1 is predicted to replace glycine with arginine at codon 84, p.(Gly84Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in the N-terminal region. There is a large physicochemical difference between glycine and arginine. This variant is present in a single European (non-Finnish) individual in gnomAD v2.1 (1/60,362 alleles). This variant has been reported in at least six probands with hereditary motor neuropathies, and segregates with disease in at least two families (PMID: 18344398, 18832141, 21892769, 27816334; Shariant). Expression of the variant in heterologous systems showed protein aggregate formation, altered protein oligomerisation, and decreased charperone-like acitivty indicating that this variant impacts protein function (PMID: 18344398, 23948568). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). The same amino acid change (p.Gly84Arg), resulting from a different nucleotide change c.250G>A, is classified as likely pathogenic for hereditary motor neuropathy (ClinVar ID: 632006). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS1, PS4_Moderate, PS3_Supporting, PM2_Supporting, PP1, PP3. -

Neuronopathy, distal hereditary motor, type 2B

Pathogenic:1

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with axonal Charcot-Marie-Tooth disease type 2F (MIM#606595) and distal hereditary motor neuronopathy 3 (MIM#608634) (PMID: 25220807). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (33 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This missense variant (and also c.250G>A) has multiple pathogenic reports in unrelated individuals (ClinVar, LOVD). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

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

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.92

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

0.99

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