chr7-76304007-C-T

Position:

• chr7-76304007-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The ENST00000248553.7(HSPB1):​c.452C>T​(p.Thr151Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T151P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPB1 ENST00000248553.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.85

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 helix (size 2) in uniprot entity HSPB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000248553.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 7-76304007-C-T is Pathogenic according to our data. Variant chr7-76304007-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76304007-C-T is described in Lovd as [Pathogenic]. Variant chr7-76304007-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-76304007-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPB1	NM_001540.5	c.452C>T	p.Thr151Ile	missense_variant	3/3	ENST00000248553.7	NP_001531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7	c.452C>T	p.Thr151Ile	missense_variant	3/3	1	NM_001540.5	ENSP00000248553	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

Aug 21, 2024

- -

Charcot-Marie-Tooth disease axonal type 2F Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 151 of the HSPB1 protein (p.Thr151Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with distal hereditary motor neuropathy or Charcot-Marie-Tooth disease (PMID: 15122254, 18325928, 28144995, 29381233). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7480). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

HSPB1: PP1:Strong, PM1, PM2, PS4:Moderate -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.73
Sift	Benign	0.17	T
Sift4G	Benign	0.18	T
Polyphen		0.92	P
Vest4		0.70
MutPred		0.74		Loss of glycosylation at T151 (P = 0.0107);
MVP		0.99
MPC		0.82
ClinPred		0.96	D
GERP RS		4.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.3
Varity_R		0.66
gMVP		0.45

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: rs28937568; hg19: chr7-75933324;