7-76302792-G-C

Variant names:

• chr7-76302792-G-C
• rs367662394
• NM_001540.5:c.80G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PM1 PP3_Moderate BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 9.10
• Publications: 5 publications found

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

ENSG00000296557 (HGNC:):

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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: 25 AN: 152180 Hom.: 0 Cov.: 33

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: 49 AN: 235340 AF XY: 0.000207

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.: 0 Cov.: 31 AF XY: 0.000306 AC XY: 222 AN XY: 724558

African (AFR) AF: 0.000149 AC: 5 AN: 33454

American (AMR) AF: 0.0000449 AC: 2 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000372 AC: 32 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49406

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5522

European-Non Finnish (NFE) AF: 0.000368 AC: 409 AN: 1111400

Other (OTH) AF: 0.000183 AC: 11 AN: 60136

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74474

African (AFR) AF: 0.0000722 AC: 3 AN: 41568

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.000212

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000251 AC: 1

ESP6500EA AF: 0.000125 AC: 1

ExAC AF: 0.000184 AC: 22

EpiCase AF: 0.000382

EpiControl AF: 0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign: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	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.97	D
Vest4		0.97
MVP		0.99
MPC		1.7
ClinPred		0.46	T
GERP RS		3.9
PromoterAI		0.034	Neutral
Varity_R		0.95
gMVP		0.98
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs367662394; hg19: chr7-75932109;