ClinVar Genomic variation as it relates to human health
NM_001540.5(HSPB1):c.544C>T (p.Pro182Ser)
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.544C>T (p.Pro182Ser)
Variation ID: 7483 Accession: VCV000007483.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.23 7: 76304099 (GRCh38) [ NCBI UCSC ] 7: 75933416 (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 Apr 15, 2024 Sep 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001540.5:c.544C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001531.1:p.Pro182Ser missense NC_000007.14:g.76304099C>T NC_000007.13:g.75933416C>T NG_008995.1:g.6542C>T LRG_248:g.6542C>T LRG_248t1:c.544C>T LRG_248p1:p.Pro182Ser - Protein change
- P182S
- Other names
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- Canonical SPDI
- NC_000007.14:76304098: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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Likely pathogenic (2) |
criteria provided, single submitter
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Mar 30, 2023 | RCV000007911.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 25, 2023 | RCV000809907.6 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease axonal type 2F
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557591.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with axonal Charcot-Marie-Tooth disease type 2F (MIM#606595) and distal hereditary motor neuronopathy type IIB (MIM#608634) (PMID: 25220807). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sHSP domain (Uniprot). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two alternative changes to an alanine or a leucine have been reported in multiple individuals with Charcot-Marie-Tooth disease or distal hereditary motor neuronopathy (ClinVar, PMID: 15122254, 27816334, 29381233). An additional change to a threonine has also been reported once as VUS in ClinVar. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals with Charcot-Marie-Tooth disease or distal hereditary motor neuronopathy, including one de novo occurrence (ClinVar, PMID: 16155736). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis shows that this variant interacts and sequestrates the WT protein and inhibiting its normal function (PMID: 25220807). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Sep 25, 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: SCV000950089.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 182 of the HSPB1 protein (p.Pro182Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 182 of the HSPB1 protein (p.Pro182Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary motor neuropathy (PMID: 16155736). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7483). 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: 25220807). This variant disrupts the p.Pro182 amino acid residue in HSPB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18325928, 27816334, 29381233). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neuronopathy, distal hereditary motor, type 2B
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503626.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace proline with serine at codon 182 of the HSPB1 protein (p.(Pro182Ser)). The proline residue is highly conserved (100 … (more)
This sequence change is predicted to replace proline with serine at codon 182 of the HSPB1 protein (p.(Pro182Ser)). The proline residue is highly conserved (100 vertebrates, UCSC), and is located in the in the IPI/V motif in the C-terminal domain. It is a critical residue for cis-trans proline isomerisation in regulating the oligomerisation of small heat shock proteins (PMID: 28547731). There is a moderate physicochemical difference between proline and serine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). It has been identified in at least three individuals with distal hereditary motor neuropathy, and one of these was confirmed de novo (PMID: 16155736, Invitae, Royal Melbourne Hospital). In functional analyses the variant induces HspB1 aggregation and decreases chaperone activity (PMID: 25220807). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Additionally, two different missense changes at the same position (Pro182Leu, Pro182Ala) have been seen in individuals with hereditary neuropathies (ClinVar). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS2_Moderate, PM1, PM2_Supporting, PS3_Supporting, PS4_Supporting, PP3. (less)
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Pathogenic
(Jan 01, 2005)
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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: SCV000028116.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
In a Japanese patient with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; 608634), Kijima et al. (2005) identified heterozygosity for a c.544C-T transition in exon … (more)
In a Japanese patient with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; 608634), Kijima et al. (2005) identified heterozygosity for a c.544C-T transition in exon 3 of the HSBP1 gene, resulting in a pro182-to-ser (P182S) substitution. The mutation was not detected in his parents or older brother or in 100 control chromosomes. (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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Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan. | Tanabe H | Journal of the peripheral nervous system : JPNS | 2018 | PMID: 29381233 |
Proline isomerization in the C-terminal region of HSP27. | Alderson TR | Cell stress & chaperones | 2017 | PMID: 28547731 |
Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene. | Rossor AM | Neuromuscular disorders : NMD | 2017 | PMID: 27816334 |
Characterization of human small heat shock protein HspB1 that carries C-terminal domain mutations associated with hereditary motor neuron diseases. | Chalova AS | Biochimica et biophysica acta | 2014 | PMID: 25220807 |
Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. | Dierick I | Brain : a journal of neurology | 2008 | PMID: 18325928 |
Small heat shock protein 27 mutation in a Japanese patient with distal hereditary motor neuropathy. | Kijima K | Journal of human genetics | 2005 | PMID: 16155736 |
Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. | Evgrafov OV | Nature genetics | 2004 | PMID: 15122254 |
Text-mined citations for rs104894020 ...
HelpRecord last updated Apr 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.