ClinVar Genomic variation as it relates to human health
NM_001540.5(HSPB1):c.250G>A (p.Gly84Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001540.5(HSPB1):c.250G>A (p.Gly84Arg)
Variation ID: 632006 Accession: VCV000632006.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.23 7: 76302962 (GRCh38) [ NCBI UCSC ] 7: 75932279 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 27, 2019 Feb 14, 2024 Aug 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001540.5:c.250G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001531.1:p.Gly84Arg missense NC_000007.14:g.76302962G>A NC_000007.13:g.75932279G>A NG_008995.1:g.5405G>A LRG_248:g.5405G>A LRG_248t1:c.250G>A - Protein change
- G84R
- Other names
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- Canonical SPDI
- NC_000007.14:76302961:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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HSPB1 | - | - |
GRCh38 GRCh37 |
368 | 408 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
no assertion criteria provided
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- | RCV000789964.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 26, 2022 | RCV001268008.5 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 30, 2023 | RCV001873176.7 | |
HSPB1-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 5, 2017 | RCV004527794.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Sep 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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HSPB1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915225.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The HSPB1 c.250G>A (p.Gly84Arg) missense variant has been reported in two studies and found in a total of three affected individuals, including in a homozygous … (more)
The HSPB1 c.250G>A (p.Gly84Arg) missense variant has been reported in two studies and found in a total of three affected individuals, including in a homozygous state in two siblings with distal hereditary motor neuropathy (dHMN) and in a presumed heterozygous state in one individual with Charcot-Marie-Tooth, type 2 (CMT2) (Manganelli et al. 2014; Ho et al. 2017). This variant was also identified in a heterozygous state in both presumably unaffected parents of the homozygous siblings. A second variant at the same nucleotide position, c.250G>C, also results in a p.Gly84Arg amino acid change and has been reported in a total of five individuals, including in a homozygous state in one individual with early onset CMT2, in a heterozygous state in two individuals with dHMN, and in a heterozygous state in the parents of the homozygous individual, both of whom displayed sub-clinical features, (James et al. 2008; Houlden et al. 2008; Fischer et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.000017 in the European (non-Finnish) population of the Genome Aggregation Database, but this is based on one allele in a region of good sequencing coverage so it is presumed to be rare. Expression of the p.Gly84Arg variant in HeLa cells led to abnormal protein aggregation (James et al. 2008), and protein interaction studies revealed that while the p.Gly84Arg variant does not affect neurofilament assembly, it does impact mobility and accessibility of the N-terminal domain, which modifies interdimer contacts in HspB1 oligomers (Nefedova et al. 2013; Nefedova et al. 2017). Based on the collective evidence, the c.250G>A (p.Gly84Arg) variant is classified as likely pathogenic for HSPB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446582.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Muscular dystrophy (present) , Gait imbalance (present)
Sex: female
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Likely pathogenic
(Aug 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease axonal type 2F
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579220.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PM2_SUP, PP1, PP3
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(May 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002770666.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has been identified in at least one individual with clinical features associated with Charcot-Marie-Tooth disease. This variant has not been reported in large, … (more)
This variant has been identified in at least one individual with clinical features associated with Charcot-Marie-Tooth disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant results in the same amino acid change as another variant (c.250G>C; p.Gly84Arg) considered to be pathogenic or likely pathogenic, strongly indicating this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was found to affect protein stability and decrease chaperone activity compared to wild-type resulting in abnormal cytoplasmic aggregation (PMID: 23948568, 31573509). (less)
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Pathogenic
(Aug 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease axonal type 2F
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002280122.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 84 of the HSPB1 protein (p.Gly84Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 84 of the HSPB1 protein (p.Gly84Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant HSPB1-related conditions (PMID: 18344398, 18832141, 21892769, 25429913). This variant has been reported in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 28379183); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 632006). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSPB1 protein function. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 18344398, 23948568). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium
Accession: SCV000929350.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Interplay of disordered and ordered regions of a human small heat shock protein yields an ensemble of 'quasi-ordered' states. | Clouser AF | eLife | 2019 | PMID: 31573509 |
Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing. | Ho CC | International journal of molecular sciences | 2017 | PMID: 28379183 |
Interaction of small heat shock proteins with light component of neurofilaments (NFL). | Nefedova VV | Cell stress & chaperones | 2017 | PMID: 28000086 |
Charcot-Marie-Tooth disease: frequency of genetic subtypes in a Southern Italy population. | Manganelli F | Journal of the peripheral nervous system : JPNS | 2014 | PMID: 25429913 |
Structure and properties of G84R and L99M mutants of human small heat shock protein HspB1 correlating with motor neuropathy. | Nefedova VV | Archives of biochemistry and biophysics | 2013 | PMID: 23948568 |
SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease. | Fischer C | Journal of neurology | 2012 | PMID: 21892769 |
Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2. | Houlden H | Neurology | 2008 | PMID: 18832141 |
Text-mined citations for rs770272088 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.