NM_001540.5:c.80G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PM1PP3_ModerateBP6BS1BS2

The NM_001540.5(HSPB1):c.80G>C(p.Arg27Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000302 in 1,608,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

HSPB1
NM_001540.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 9.10

Publications

5 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: Likely_benign. The variant received -5 ACMG points.

PM1

In a chain Heat shock protein beta-1 (size 204) in uniprot entity HSPB1_HUMAN there are 29 pathogenic changes around while only 8 benign (78%) in NM_001540.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

BP6

Variant 7-76302792-G-C is Benign according to our data. Variant chr7-76302792-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245625.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000316 (460/1456266) while in subpopulation SAS AF = 0.000372 (32/86090). AF 95% confidence interval is 0.000338. There are 0 homozygotes in GnomAdExome4. There are 222 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 25 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.80G>C	p.Arg27Pro	missense	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.80G>C	p.Arg27Pro	missense	Exon 1 of 3	ENSP00000248553.6
HSPB1	ENST00000447574.1	TSL:1	n.105G>C		non_coding_transcript_exon	Exon 1 of 2
HSPB1	ENST00000676231.2		c.80G>C	p.Arg27Pro	missense	Exon 1 of 4	ENSP00000502249.1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000208

AC:

AN:

235340

AF XY:

0.000207

show subpopulations

Gnomad AFR exome

AF:

0.000292

Gnomad AMR exome

AF:

0.0000883

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000236

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000316

AC:

460

AN:

1456266

Hom.:

Cov.:

AF XY:

0.000306

AC XY:

222

AN XY:

724558

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33454

American (AMR)

AF:

0.0000449

AC:

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.000372

AC:

AN:

86090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49406

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

0.000368

AC:

409

AN:

1111400

Other (OTH)

AF:

0.000183

AC:

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000164

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41568

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000185

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000251

AC:

ESP6500EA

AF:

0.000125

AC:

ExAC

AF:

0.000184

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Mar 09, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg27Pro variant (rs367662394) variant was reported in one patient in a CMT cohort referred to for genetic testing (DiVincenzo 2014). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.06 percent in the South Asian population (identified on 17 out of 30,440 chromosomes). The arginine at position 27 is highly conserved up to fruitfly considering 12 species and computational analyses of the p.Arg27Pro variant on protein structure and function indicate a deleterious effect (SIFT: damaging, PolyPhen-2:possibly damaging). Altogether, there is not enough evidence to classify the p.Arg27Pro variant with certainty.

May 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 04, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 22, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R27P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, nor with any significant frequency in the 1000 Genomes Project. The R27P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant

Charcot-Marie-Tooth disease

Uncertain:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Sep 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HSPB1 c.80G>C (p.Arg27Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 235340 control chromosomes, predominantly at a frequency of 0.00056 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in HSPB1 causing Charcot-Marie Disease Axonal Type 2F, allowing no conclusion about variant significance. c.80G>C has been reported in the literature in individuals affected with Charcot-Marie Disease and congenital heart defects, without strong evidence for causality (Russell_2019, Volodarsky_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Charcot-Marie Disease Axonal Type 2F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31453292, 32376792). ClinVar contains an entry for this variant (Variation ID: 245625). Based on the evidence outlined above, the variant was classified as uncertain significance.

HSPB1-related disorder

Uncertain:1

Feb 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The HSPB1 c.80G>C variant is predicted to result in the amino acid substitution p.Arg27Pro. This variant was reported in an individual with congenital heart defect who also carries a missense variant in the CCR3 gene (Table 2, Russell et al 2019. PubMed ID: 31453292.) In addition, this variant was reported twice in a Canadian cohort study of Charcot-Marie-Tooth disease and was classified as uncertain (Supplementary table 2, Volodarsky M et al 2020. PubMed ID: 32376792). This variant is reported in 0.056% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Inborn genetic diseases

Benign:1

Jul 26, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Charcot-Marie-Tooth disease axonal type 2F

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.0

PhyloP100

9.1

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.97

Vest4

0.97

MVP

0.99

MPC

1.7

ClinPred

0.46

GERP RS

3.9

PromoterAI

0.034

Neutral

(source)

Varity_R

0.95

gMVP

0.98

Mutation Taster

=58/42

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over