7-76302886-GC-GCC

Position:

• chr7-76302886-GC-GCC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001540.5(HSPB1):​c.180dupC​(p.Ala61fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,559,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: HSPB1 NM_001540.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.897

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-76302886-G-GC is Pathogenic according to our data. Variant chr7-76302886-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 423339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPB1	NM_001540.5	c.180dupC	p.Ala61fs	frameshift_variant	1/3	ENST00000248553.7	NP_001531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7	c.180dupC	p.Ala61fs	frameshift_variant	1/3	1	NM_001540.5	ENSP00000248553.6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152040 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000620 AC: 1 AN: 161418 Hom.: 0 AF XY: 0.0000112 AC XY: 1 AN XY: 89614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000403

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000320 AC: 45 AN: 1407166 Hom.: 0 Cov.: 31 AF XY: 0.0000258 AC XY: 18 AN XY: 696614

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: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000394

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152040 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74274

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2018	The c.180dupC variant in the HSPB1 gene causes a frameshift starting with codon Alanine 61, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 100 of the new reading frame, denoted p.Ala61ArgfsX100. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 145 amino acids of the HSPB1 protein are lost and replaced with 99 incorrect amino acids. Multiple variants are noted in the last 145 amino acid residues of the HSPB1 protein in the Human Gene Mutation Database in association with HSPB1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 30, 2021	- -

HSPB1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2024

The HSPB1 c.180dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala61Argfs*100). This variant has been reported in an individual with distal hereditary motor neuropathy (dHMN); and the functional analysis did not show expression of the protein upon HSPB1 staining in HeLa cells (F13 in Table 1 of Echaniz-Laguna et al. 2017. PubMed ID: 28144995). This variant is reported in 0.0040% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in HSPB1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the region of the HSPB1 protein between p.Pro39Leu and p.Pro182Ala. Other variants in this region have been observed in individuals with autosomal dominant HSPB1-related conditions (PMID: 22734906, 28144995, 29381233), which suggests that this may be a clinically significant region of the protein. ClinVar contains an entry for this variant (Variation ID: 423339). This premature translational stop signal has been observed in individual(s) with autosomal dominant distal hereditary motor neuropathy (PMID: 28144995). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ala61Argfs*100) in the HSPB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 145 amino acid(s) of the HSPB1 protein. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Biochimie - Maladies Neurologiques Hereditaires, Hospices Civils de Lyon

Feb 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs1064796370; hg19: chr7-75932203;