7-76304099-C-G

Variant names:

• chr7-76304099-C-G
• rs104894020
• NM_001540.5:c.544C>G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001540.5(HSPB1):​c.544C>G​(p.Pro182Ala) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P182S) 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:2
• 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 16 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 7-76304099-C-G is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB1	NM_001540.5	c.544C>G	p.Pro182Ala	missense_variant	Exon 3 of 3	ENST00000248553.7	NP_001531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7	c.544C>G	p.Pro182Ala	missense_variant	Exon 3 of 3	1	NM_001540.5	ENSP00000248553.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jun 04, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with alanine at codon 182 of the HSPB1 protein (p.Pro182Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hereditary motor neuropathy in two families (PMID: 27816334, 29381233). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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, 16155736, 25220807). 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. -

Jul 20, 2021

Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

4. The p.Pro182Ala variant in HSPB1 has already been described in the literature and is one of the three pathogenic variants at this amino acid residue (p.Pro182Leu and p.Pro182Ser). Patients usually present with an AD-CMT2F (OMIM: 606595) or an exclusively motor neuropathy (AD-dHMN2B; OMIM: 608634) with variable age of onset (6-54 years). ClinVar classifies this variant as Pathogenic (Variation ID: 946496), 1 star (criteria provided, 1 submission), citing 5 articles (29381233, 27816334, 25220807, 18325928 and 16155736). This variant is in a hotspot region and an important functional domain of the protein (C-terminal' anchoring motif'). This amino acid residue is highly conserved in different species. Besides that, this variant segregates with family phenotype. In summary, the p.Pro182Ala meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;.
Vest4		0.55
MutPred		0.78		Loss of disorder (P = 0.1412);.;
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		0.80

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;