chr7-76304099-C-T

Position:

• chr7-76304099-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001540.5(HSPB1):​c.544C>T​(p.Pro182Ser) 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. P182L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.47

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 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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 chr7-76304099-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 946496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 7-76304099-C-T is Pathogenic according to our data. Variant chr7-76304099-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76304099-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-76304099-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB1	NM_001540.5	c.544C>T	p.Pro182Ser	missense_variant	3/3	ENST00000248553.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB1	ENST00000248553.7	c.544C>T	p.Pro182Ser	missense_variant	3/3	1	NM_001540.5	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 axonal type 2F Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 25, 2023	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 182 of the HSPB1 protein (p.Pro182Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary motor neuropathy (PMID: 16155736). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7483). 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: 25220807). This variant disrupts the p.Pro182 amino acid residue in HSPB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18325928, 27816334, 29381233). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with axonal Charcot-Marie-Tooth disease type 2F (MIM#606595) and distal hereditary motor neuronopathy type IIB (MIM#608634) (PMID: 25220807). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sHSP domain (Uniprot). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two alternative changes to an alanine or a leucine have been reported in multiple individuals with Charcot-Marie-Tooth disease or distal hereditary motor neuronopathy (ClinVar, PMID: 15122254, 27816334, 29381233). An additional change to a threonine has also been reported once as VUS in ClinVar. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals with Charcot-Marie-Tooth disease or distal hereditary motor neuronopathy, including one de novo occurrence (ClinVar, PMID: 16155736). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis shows that this variant interacts and sequestrates the WT protein and inhibiting its normal function (PMID: 25220807). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace proline with serine at codon 182 of the HSPB1 protein (p.(Pro182Ser)). The proline residue is highly conserved (100 vertebrates, UCSC), and is located in the in the IPI/V motif in the C-terminal domain. It is a critical residue for cis-trans proline isomerisation in regulating the oligomerisation of small heat shock proteins (PMID: 28547731). There is a moderate physicochemical difference between proline and serine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). It has been identified in at least three individuals with distal hereditary motor neuropathy, and one of these was confirmed de novo (PMID: 16155736, Invitae, Royal Melbourne Hospital). In functional analyses the variant induces HspB1 aggregation and decreases chaperone activity (PMID: 25220807). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Additionally, two different missense changes at the same position (Pro182Leu, Pro182Ala) have been seen in individuals with hereditary neuropathies (ClinVar). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS2_Moderate, PM1, PM2_Supporting, PS3_Supporting, PS4_Supporting, PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2005	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.91
Sift	Benign	0.038	D;D
Sift4G	Uncertain	0.060	T;D
Polyphen		1.0	D;.
Vest4		0.62
MutPred		0.86		Gain of sheet (P = 0.1451);.;
MVP		1.0
MPC		1.5
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.84

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: rs104894020; hg19: chr7-75933416; COSMIC: COSV50349761;