rs770272088

chr7-76302962-G-Achr7-76302962-G-Cchr7-76302962-G-T

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_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. 12/20 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 ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G84E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 5.12

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 26 ACMG points.

• PS1: Transcript NM_001540.5 (HSPB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 220419
• PM1: In a domain sHSP (size 108) in uniprot entity HSPB1_HUMAN there are 48 pathogenic changes around while only 4 benign (92%) in NM_001540.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-76302962-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 948718.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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	UniProt
HSPB1	NM_001540.5	c.250G>A	p.Gly84Arg	missense_variant	1/3	ENST00000248553.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB1	ENST00000248553.7	c.250G>A	p.Gly84Arg	missense_variant	1/3	1	NM_001540.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1392122 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 687784

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.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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 Disorders 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.81		Gain of solvent accessibility (P = 0.0128);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs770272088; hg19: chr7-75932279;