rs121909112

chr7-76303855-C-G

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.418C>G(p.Arg140Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000242 in 1,240,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.93

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001540.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-76303855-C-G is Pathogenic according to our data. Variant chr7-76303855-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 7484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76303855-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB1	NM_001540.5	c.418C>G	p.Arg140Gly	missense_variant	2/3	ENST00000248553.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB1	ENST00000248553.7	c.418C>G	p.Arg140Gly	missense_variant	2/3	1	NM_001540.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000242 AC: 3 AN: 1240538 Hom.: 0 Cov.: 36 AF XY: 0.00000486 AC XY: 3 AN XY: 617200

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: 0.0000361

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 13, 2020	PS3, PS4_moderate, PM1, PM2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2023	This variant has been identified in multiple unrelated individuals with clinical features associated with CMT or hereditary motor neuropathy. 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: 23643870, 28595321) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2023	Published functional studies demonstrate a damaging effect, including decreased chaperone-like activity and impaired mitochondrial function in motor neurons (Nefedova et al., 2013; Kalmar et al., 2017); 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: 28000086, 26989944, 23643870, 27933579, 28389817, 15706088, 27816334, 26752306, 23379525, 28595321, 29547183, 32376792, 18832141, 28702508, 31561939) -

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 140 of the HSPB1 protein (p.Arg140Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with distal vacuolar myopathy and motor neuropathy and Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) (PMID: 18832141, 27816334, 28702508). ClinVar contains an entry for this variant (Variation ID: 7484). 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: 23643870, 28595321). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 27, 2019	A heterozygous missense variation in the exon 2 of the HSPB1 gene that results in the amino acid substitution of Glycine for Arginine at codon 140 was detected. The observed variant c.418C>G (p.Arg140Gly) has not been reported in 1000 genomes and ExAC databases. The in silico predictions of the variant are damaging by SIFT, LRT and MutationTaster2. The observed variant has previously been reported in patients affected with Charcot-Marie-Tooth disease type 2 (Holden et al 2008 Neurology). Furthermore, functional studies have shown that the said variant affects the quaternary structure and decreases the chaperon like activity of the protein (Nefedova et al 2013 Biochimie). In summary, the said variant meets our criteria to be classified as pathogenic. -

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2020

The p.R140G variant (also known as c.418C>G), located in coding exon 2 of the HSPB1 gene, results from a C to G substitution at nucleotide position 418. The arginine at codon 140 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been described in multiple unrelated individuals diagnosed with distal hereditary motor neuropathy (dHMN), Charcot-Marie-Tooth type 2 (CMT2), and a syndrome overlapping both dHMN/CMT2 clinical symptoms (Ghodasara MK et al. Neurol India;66:528-529; Houlden H et al. Neurology, 2008 Nov;71:1660-8; Luigetti M et al. Clin Neurol Neurosurg, 2016 May;144:67-71; Rossor AM et al. Neuromuscul Disord, 2017 Jan;27:50-56; Tanabe H et al. J Peripher Nerv Syst, 2018 03;23:40-48). A patient who presented with vacuolar myopathy and axonal motor neuropathy was described as homozygous for this alteration. Parents were mildly affected upon clinical examination in their 80s (Bugiardini E et al. Neurol Genet, 2017 Aug;3:e168). Functional studies suggest this alteration impairs mitochondrial function and results in a reduction of chaperone-like activity (Kalmar B et al. Hum Mol Genet 2017 Sep; 26:3313-3326; Nefedova V et al. Biochimie 2013 Aug;95:1582-1592). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Neuronopathy, distal hereditary motor, type 2B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 18, 2008

- -

HSPB1-related axonal neuropathies Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 12, 2021

The HSPB1 c.418C>G (p.Arg140Gly) variant is a missense variant. Across a selection of the available literature, the p.Arg140Gly variant has been identified in a heterozygous state in seven index cases from at least three diverse populations with late onset Charcot-Marie-Tooth disease or hereditary motor neuronopathy (Houlden et al. 2008; Luigetti et al. 2016; Tanabe et al. 2018; Peddareddygari et al. 2019). The p.Arg140Gly was noted to segregate with disease in seven affected family members across two generations in a large pedigree originating from the Gujarat region of India (Peddareddygari et al. 2019). The p.Arg140Gly variant has been reported in at least four additional families from this region, leading to speculation that it may be a founder variant in this group (Rosser et al 2017; Peddareddygari et al. 2019). The p.Arg140Gly variant was also identified in a homozygous state in a 57-year-old female with distal vacuolar myopathy and motor neuropathy, first manifesting at 20 years of age (Bugiardini et al. 2017). Clinical examination of the proband's parents, both in their eighties, revealed mild distal weakness in the upper and lower limbs with areflexia, demonstrating the clinical variability associated with this variant. The p.Arg140Gly variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequence coverage, which suggests the variant is rare. The Arg140 residue is located within the beta 7 strand of a-crystallin domain of HspB1 protein and predicted to disrupt the quaternary structure of HspB1, decreasing its chaperone like activity (Nefedova et al. 2013). Experiments expressing the variant in a heterologous state using a lentiviral system in primary cultured mouse motor neurons showed that, in this model, p.Arg140Gly reduced the speed and altered the pausing frequency of retrograde axonal mitochondrial transport, leading to an increased vulnerability of these cells to oxidative stress (Kalmar et al. 2017). Based on the available evidence, the p.Arg140Gly variant is classified as pathogenic for HSPB1-related axonal neuropathies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.15	B
Vest4		0.93
MutPred		0.97		Loss of methylation at K141 (P = 0.0471);
MVP		0.99
MPC		0.74
ClinPred		0.90	D
GERP RS		3.5
Varity_R		0.97
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121909112; hg19: chr7-75933172; COSMIC: COSV105065418;