7-76303841-C-T

Variant names:

• chr7-76303841-C-T
• rs28939680
• NM_001540.5:c.404C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001540.5(HSPB1):​c.404C>T​(p.Ser135Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S135C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 5.22
• Publications: 70 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2F

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
• neuronopathy, distal hereditary motor, type 2B

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• distal hereditary motor neuropathy type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain 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 chr7-76303841-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 637060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 7-76303841-C-T is Pathogenic according to our data. Variant chr7-76303841-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB1	NM_001540.5	c.404C>T	p.Ser135Phe	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.404C>T	p.Ser135Phe	missense_variant	Exon 2 of 3	1	NM_001540.5	ENSP00000248553.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: 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:3

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007478). Different missense changes at the same codon (p.Ser135Cys, p.Ser135Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000533813, VCV000637060). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 18, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser135 amino acid residue in HSPB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23963299). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 15122254, 17881652). 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) performed at Invitae indicates that this missense variant is expected to disrupt HSPB1 protein function. ClinVar contains an entry for this variant (Variation ID: 7478). This missense change has been observed in individual(s) with autosomal dominant axonal Charcot-Marie-Tooth (CMT2) and distal hereditary motor neuronopathy type 2B (dHMN2B) (PMID: 15122254, 18832141). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 135 of the HSPB1 protein (p.Ser135Phe). -

not provided Pathogenic:1

Aug 15, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15122254, 17881652, 20178975, 21785432) -

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

Nov 18, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.2
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.88	P
Vest4		0.96
MutPred		0.84		Loss of disorder (P = 0.0362);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		0.13	Neutral
Varity_R		0.97
gMVP		0.80
Mutation Taster		=202/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28939680; hg19: chr7-75933158; COSMIC: COSV107216017;