chr7-76303855-C-G

Variant names:

• chr7-76303855-C-G
• rs121909112
• NM_001540.5:c.418C>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:12
• 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 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, 0.992
• 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 rank	MANE	Protein	UniProt
HSPB1	NM_001540.5	c.418C>G	p.Arg140Gly	missense_variant	Exon 2 of 3	ENST00000248553.7	NP_001531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7	c.418C>G	p.Arg140Gly	missense_variant	Exon 2 of 3	1	NM_001540.5	ENSP00000248553.6

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

May 03, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM1, PM2, PP4 -

Jun 28, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 26, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:3

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 27, 2019

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HSPB1 c.418C>G (p.Arg140Gly) results in a non-conservative amino acid change located in the Small heat shock protein (sHSP) domain (IPR002068) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249274 control chromosomes. c.418C>G has been reported in the literature in individuals affected with Charcot-Marie-Tooth disease or Distal hereditary motor neuropathy (example, Wu_2022, Khadilkar_2017, Lupo_2016). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significantly diminished normal HSPB1 activity, forming aggregates, and loss of the binding with wide-type HspB6 in vitro (Nefedova_2013). The following publications have been ascertained in the context of this evaluation (PMID: 29184351, 28018906, 23948568, 35297556). ClinVar contains an entry for this variant (Variation ID: 7484). Based on the evidence outlined above, the variant was classified as pathogenic. -

Charcot-Marie-Tooth disease Pathogenic:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Dec 08, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 18, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HSPB1-related axonal neuropathies Pathogenic:1

Aug 12, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Charcot-Marie-Tooth disease axonal type 2F;C2608087:Neuronopathy, distal hereditary motor, type 2B Pathogenic:1

Apr 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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;