ClinVar Genomic variation as it relates to human health
NM_001540.5(HSPB1):c.404C>T (p.Ser135Phe)
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.404C>T (p.Ser135Phe)
Variation ID: 7478 Accession: VCV000007478.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.23 7: 76303841 (GRCh38) [ NCBI UCSC ] 7: 75933158 (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 Apr 4, 2013 Feb 14, 2024 Aug 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001540.5:c.404C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001531.1:p.Ser135Phe missense NC_000007.14:g.76303841C>T NC_000007.13:g.75933158C>T NG_008995.1:g.6284C>T LRG_248:g.6284C>T LRG_248t1:c.404C>T LRG_248p1:p.Ser135Phe P04792:p.Ser135Phe - Protein change
- S135F
- Other names
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- Canonical SPDI
- NC_000007.14:76303840:C:T
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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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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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Pathogenic (1) |
no assertion criteria provided
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Nov 18, 2008 | RCV000007905.5 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 17, 2023 | RCV000007904.10 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000789332.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2023 | RCV003482225.1 |
Submissions - Germline
Classification
Help
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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Pathogenic
(May 22, 2022)
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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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3billion
Accession: SCV002521244.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007478). Different missense changes at the same codon (p.Ser135Cys, p.Ser135Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000533813, VCV000637060). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Stroke disorder (present)
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Pathogenic
(Aug 15, 2023)
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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 Inc
Accession: SCV004229710.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
This variant has not been reported in large, multi-ethnic general populations. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this … (more)
This variant has not been reported in large, multi-ethnic general populations. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15122254, 17881652, 20178975, 21785432) (less)
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Pathogenic
(Jun 17, 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: SCV001586034.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 135 of the HSPB1 protein (p.Ser135Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 135 of the HSPB1 protein (p.Ser135Phe). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser135 amino acid residue in HSPB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23963299). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 15122254, 17881652). 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) performed at Invitae indicates that this missense variant is expected to disrupt HSPB1 protein function. ClinVar contains an entry for this variant (Variation ID: 7478). This missense change has been observed in individual(s) with autosomal dominant axonal Charcot-Marie-Tooth (CMT2) and distal hereditary motor neuronopathy type 2B (dHMN2B) (PMID: 15122254, 18832141). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). (less)
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Pathogenic
(Nov 18, 2008)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028109.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
In affected members of a Russian family with Charcot-Marie-Tooth disease type 2F (CMT2F; 606595) previously reported by Ismailov et al. (2001), Evgrafov et al. (2004) … (more)
In affected members of a Russian family with Charcot-Marie-Tooth disease type 2F (CMT2F; 606595) previously reported by Ismailov et al. (2001), Evgrafov et al. (2004) identified a heterozygous c.404C-T transition in exon 2 of the HSPB1 gene, resulting in a ser135-to-phe (S135F) substitution. In affected members of an unrelated family from the United Kingdom with autosomal dominant distal hereditary motor neuronopathy 3 (HMND3; 608634), the authors identified the same mutation in heterozygosity. The S135F mutation occurs in a highly conserved alpha-crystallin domain of the protein. In vitro expression of the mutant protein resulted in reduced viability of neuronal cells and impaired neurofilament assembly. Evgrafov et al. (2004) suggested that these deficits may be responsible for premature axonal degeneration, which underlies both CMT and dHMN. Houlden et al. (2008) identified a heterozygous S135F mutation in affected members of a large family with HMND3. The mean age at onset was 21 years, and sensory abnormalities were not present. Variant Function In cultured mouse motor neurons, Zhai et al. (2007) showed that expression of S135F-mutant HSPB1 led to progressive degeneration of motor neurons with disruption of the neurofilament network and aggregation of NEFL (162280) protein. The 2 proteins were found to associate together, and the S135F mutant had a dominant effect. Similarly, expression of NEFL mutants (e.g., 162280.0003) also led to disruption of the neurofilament network and aggregation of NEFL, and wildtype HSPB1 induced reversal of NEFL aggregates. Zhai et al. (2007) suggested that disruption of the neurofilament network with aggregation of NEFL is a common triggering event of motor neuron degeneration in CMT2E (607684) and CMT2F. (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: SCV000928685.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
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Pathogenic
(Nov 18, 2008)
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no assertion criteria provided
Method: literature only
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV004046652.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment on evidence:
In affected members of a Russian family with Charcot-Marie-Tooth disease type 2F (CMT2F; 606595) previously reported by Ismailov et al. (2001), Evgrafov et al. (2004) … (more)
In affected members of a Russian family with Charcot-Marie-Tooth disease type 2F (CMT2F; 606595) previously reported by Ismailov et al. (2001), Evgrafov et al. (2004) identified a heterozygous c.404C-T transition in exon 2 of the HSPB1 gene, resulting in a ser135-to-phe (S135F) substitution. In affected members of an unrelated family from the United Kingdom with autosomal dominant distal hereditary motor neuronopathy 3 (HMND3; 608634), the authors identified the same mutation in heterozygosity. The S135F mutation occurs in a highly conserved alpha-crystallin domain of the protein. In vitro expression of the mutant protein resulted in reduced viability of neuronal cells and impaired neurofilament assembly. Evgrafov et al. (2004) suggested that these deficits may be responsible for premature axonal degeneration, which underlies both CMT and dHMN. Houlden et al. (2008) identified a heterozygous S135F mutation in affected members of a large family with HMND3. The mean age at onset was 21 years, and sensory abnormalities were not present. Variant Function In cultured mouse motor neurons, Zhai et al. (2007) showed that expression of S135F-mutant HSPB1 led to progressive degeneration of motor neurons with disruption of the neurofilament network and aggregation of NEFL (162280) protein. The 2 proteins were found to associate together, and the S135F mutant had a dominant effect. Similarly, expression of NEFL mutants (e.g., 162280.0003) also led to disruption of the neurofilament network and aggregation of NEFL, and wildtype HSPB1 induced reversal of NEFL aggregates. Zhai et al. (2007) suggested that disruption of the neurofilament network with aggregation of NEFL is a common triggering event of motor neuron degeneration in CMT2E (607684) and CMT2F. (less)
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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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Genetic and Clinical Studies of Peripheral Neuropathies with Three Small Heat Shock Protein Gene Variants in Korea. | Lim SO | Genes | 2022 | PMID: 35328016 |
Charcot-Marie-Tooth disease type 2F associated with biallelic HSPB1 mutations. | Abati E | Annals of clinical and translational neurology | 2021 | PMID: 33943041 |
Mutations in heat shock protein beta-1 (HSPB1) are associated with a range of clinical phenotypes related to different patterns of motor neuron dysfunction: A case series. | Katz M | Journal of the neurological sciences | 2020 | PMID: 32334137 |
Human HSPB1 mutation recapitulates features of distal hereditary motor neuropathy (dHMN) in Drosophila. | Kang KH | Biochemical and biophysical research communications | 2020 | PMID: 31630804 |
Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations. | Echaniz-Laguna A | Human mutation | 2017 | PMID: 28144995 |
HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation. | Kim JY | Stem cells international | 2016 | PMID: 28105056 |
Targeted next-generation sequencing reveals further genetic heterogeneity in axonal Charcot-Marie-Tooth neuropathy and a mutation in HSPB1. | Ylikallio E | European journal of human genetics : EJHG | 2014 | PMID: 23963299 |
Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease. | Lee HS | Clinical and experimental reproductive medicine | 2013 | PMID: 24505562 |
HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. | d'Ydewalle C | Nature medicine | 2011 | PMID: 21785432 |
Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-Tooth neuropathy. | Almeida-Souza L | The Journal of biological chemistry | 2010 | PMID: 20178975 |
Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2. | Houlden H | Neurology | 2008 | PMID: 18832141 |
Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1. | Zhai J | Human molecular genetics | 2007 | PMID: 17881652 |
Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. | Evgrafov OV | Nature genetics | 2004 | PMID: 15122254 |
A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21. | Ismailov SM | European journal of human genetics : EJHG | 2001 | PMID: 11528513 |
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Text-mined citations for rs28939680 ...
HelpRecord last updated Feb 20, 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.