chr7-76302886-G-GC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2

The NM_001540.5(HSPB1):c.180dupC(p.Ala61ArgfsTer100) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A61A) has been classified as Likely benign. 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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.897

Publications

3 publications found

Variant links:

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

HSPB1 links:

ENSG00000296557 (HGNC:):

ENSG00000296557 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 423339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 45 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001540.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB1	NM_001540.5	MANE Select	c.180dupC	p.Ala61ArgfsTer100	frameshift	Exon 1 of 3	NP_001531.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HSPB1	ENST00000248553.7	TSL:1 MANE Select	c.180dupC	p.Ala61ArgfsTer100	frameshift	Exon 1 of 3	ENSP00000248553.6
HSPB1	ENST00000447574.1	TSL:1	n.205dupC		non_coding_transcript_exon	Exon 1 of 2
HSPB1	ENST00000676231.2		c.180dupC	p.Ala61ArgfsTer110	frameshift	Exon 1 of 4	ENSP00000502249.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00000620

AC:

AN:

161418

AF XY:

0.0000112

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000320

AC:

AN:

1407166

Hom.:

Cov.:

AF XY:

0.0000258

AC XY:

AN XY:

696614

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32428

American (AMR)

AF:

0.00

AC:

AN:

38408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25284

East Asian (EAS)

AF:

0.00

AC:

AN:

37262

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5012

European-Non Finnish (NFE)

AF:

0.0000394

AC:

AN:

1090216

Other (OTH)

AF:

0.0000171

AC:

AN:

58486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Nov 30, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 18, 2018

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

HSPB1-related disorder

Pathogenic:1

Apr 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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 premature translational stop signal has been observed in individual(s) with autosomal dominant distal hereditary motor neuropathy (PMID: 28144995). ClinVar contains an entry for this variant (Variation ID: 423339). This variant is located in a region of the HSPB1 protein where a significant number of HSPB1 nonsense and frameshift mutations have been reported in association with autosomal dominant HSPB1-related neuropathies (PMID: 22734906, 28144995, 33686258). For these reasons, this variant has been classified as Pathogenic.

Neuronopathy, distal hereditary motor, type 2B

Pathogenic:1

Feb 02, 2017

Biochimie - Maladies Neurologiques Hereditaires, Hospices Civils de Lyon

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.90

Mutation Taster

=8/192

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over