ClinVar Genomic variation as it relates to human health
NM_005861.4(STUB1):c.433A>C (p.Lys145Gln)
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.
Pathogenic(3); Likely pathogenic(2); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005861.4(STUB1):c.433A>C (p.Lys145Gln)
Variation ID: 212325 Accession: VCV000212325.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 681512 (GRCh38) [ NCBI UCSC ] 16: 731512 (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 Oct 5, 2015 Feb 14, 2024 Dec 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005861.4:c.433A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005852.2:p.Lys145Gln missense NM_001293197.2:c.217A>C NP_001280126.1:p.Lys73Gln missense NC_000016.10:g.681512A>C NC_000016.9:g.731512A>C NG_034141.1:g.6402A>C Q9UNE7:p.Lys145Gln - Protein change
- K145Q, K73Q
- Other names
- STUB1, LYS145GLN (rs146251364)
- Canonical SPDI
- NC_000016.10:681511:A:C
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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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0.00060 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054
The Genome Aggregation Database (gnomAD), exomes 0.00059
1000 Genomes Project 0.00060
Trans-Omics for Precision Medicine (TOPMed) 0.00054
The Genome Aggregation Database (gnomAD) 0.00063
Exome Aggregation Consortium (ExAC) 0.00070
1000 Genomes Project 30x 0.00078
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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STUB1 | - | - |
GRCh38 GRCh37 |
73 | 242 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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) |
criteria provided, single submitter
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Jun 27, 2014 | RCV000194931.13 | |
Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Mar 21, 2023 | RCV000989407.21 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 22, 2022 | RCV002517140.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 17, 2023 | RCV002517982.9 |
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
Help
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
Help
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
Help
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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Uncertain significance
(Jun 27, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000249062.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive spinocerebellar ataxia 16
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139727.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Jan 04, 2021)
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criteria provided, single submitter
Method: research
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Autosomal recessive spinocerebellar ataxia 16
Affected status: yes
Allele origin:
unknown
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Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519220.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
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Uncertain significance
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003539602.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.433A>C (p.K145Q) alteration is located in exon 3 (coding exon 3) of the STUB1 gene. This alteration results from a A to C substitution … (more)
The c.433A>C (p.K145Q) alteration is located in exon 3 (coding exon 3) of the STUB1 gene. This alteration results from a A to C substitution at nucleotide position 433, causing the lysine (K) at amino acid position 145 to be replaced by a glutamine (Q). This alteration has been reported in multiple individuals with features of STUB1-related spinocerebellar ataxia (Benkirane, 2021; Coutelier, 2017; Sun, 2019). Functional analysis demonstrated reduced CHIP protein levels in cortical neurons derived from patient fibroblasts containing c.433A>C (p.K145Q) and c.728C>T (p.P243L) in the compound heterozygote state (Schuster, 2020). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive spinocerebellar ataxia 16
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003808100.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PM3 strong, PP1 moderated
Number of individuals with the variant: 1
Clinical Features:
Visual impairment (present) , Progressive gait ataxia (present) , Limb ataxia (present) , Dysmetria (present) , Gait ataxia (present) , Morphological central nervous system abnormality … (more)
Visual impairment (present) , Progressive gait ataxia (present) , Limb ataxia (present) , Dysmetria (present) , Gait ataxia (present) , Morphological central nervous system abnormality (present) , Lower limb dysmetria (present) , Upper limb dysmetria (present) , Hearing impairment (present) , Cerebellar ataxia (present) , Progressive cerebellar ataxia (present) , Limb dysmetria (present) , Dysdiadochokinesis (present) , Spasticity (present) , Atrophy/Degeneration affecting the central nervous system (present) , Lower limb spasticity (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Likely pathogenic
(Mar 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive spinocerebellar ataxia 16
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003927232.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
This STUB1 variant (rs146251364) is rare (<0.1%) in a large population dataset (gnomAD 171/280402 total alleles; 0.06%; 1 homozygote) and has been reported in ClinVar. … (more)
This STUB1 variant (rs146251364) is rare (<0.1%) in a large population dataset (gnomAD 171/280402 total alleles; 0.06%; 1 homozygote) and has been reported in ClinVar. This missense change has been observed in individuals with clinical features of spinocerebellar ataxia, autosomal recessive 16 (SCAR16) and has been observed to segregate with disease in families. In vitro studies using transfected cells have shown that this missense change has a moderate effect on STUB1 function. However, functional analysis in cortical neurons derived from patient fibroblasts containing c.433A>C (p.Lys145Gln) and c.728C>T (p.Pro243Leu) in the compound heterozygote state demonstrated reduced STUB1/CHIP protein levels. Bioinformatic analysis predicts that this missense variant would not affect normal exon 3 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.433A>C (p.Lys145Gln) to be likely pathogenic for SCAR16. (less)
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Pathogenic
(Aug 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive spinocerebellar ataxia 16
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045861.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Gait ataxia (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present)
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Pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Autosomal recessive spinocerebellar ataxia 16
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004046810.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
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Uncertain significance
(Dec 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003262075.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 145 of the STUB1 protein (p.Lys145Gln). … (more)
This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 145 of the STUB1 protein (p.Lys145Gln). This variant is present in population databases (rs146251364, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of autosomal recessive spinocerebellar ataxia (PMID: 24719489, 28193272, 28193273, 28444220, 29915382, 32367277, 33417001, 34663476). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 212325). 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 not expected to disrupt STUB1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect STUB1 function (PMID: 28396517, 29317501). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Feb 25, 2021)
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no assertion criteria provided
Method: literature only
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SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 16
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001481843.1
First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021 |
Comment on evidence:
In 2 Belgian brothers with autosomal recessive spinocerebellar ataxia-16 (SCAR16; 615768), Depondt et al. (2014) identified compound heterozygous mutations in the STUB1 gene: a c.433A-C … (more)
In 2 Belgian brothers with autosomal recessive spinocerebellar ataxia-16 (SCAR16; 615768), Depondt et al. (2014) identified compound heterozygous mutations in the STUB1 gene: a c.433A-C transversion in exon 3, resulting in a lys145-to-gln (K145Q) substitution at a highly conserved residue, and a 4-bp deletion in exon 6 (c.687_690delCTAC; 607207.0015), predicted to result in a frameshift and premature termination (Tyr230CysfsTer8) before the U-box domain. This deletion was also predicted to lead to nonsense-mediated mRNA decay and complete loss of the STUB1 protein. The mutations were found by whole-exome sequencing: K145Q was present in the heterozygous state at a low frequency (0.00054) in the Exome Variant Server database (7 of 12,979 chromosomes), whereas the 4-bp deletion was not listed in the database. Functional expression studies of the variants and studies of patient cells were not performed. It was not clear from the report whether or not the parents carried the mutations, but they were noted to be unaffected. Ravel et al. (2021) found the K145Q mutation in compound heterozygosity with another missense mutation in 2 sisters (family 2) with SCAR16. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive spinocerebellar ataxia 16
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760377.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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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 spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias. | Cheng HL | Translational neurodegeneration | 2021 | PMID: 34663476 |
High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families. | Benkirane M | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34234304 |
Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia. | Ravel JM | Journal of neurology | 2021 | PMID: 33417001 |
CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons. | Schuster S | Disease models & mechanisms | 2020 | PMID: 33097556 |
Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan. | Chiu HH | Cerebellum (London, England) | 2020 | PMID: 32367277 |
Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. | Sun M | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29915382 |
Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP. | Kanack AJ | The Journal of biological chemistry | 2018 | PMID: 29317501 |
A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies. | Coutelier M | Brain : a journal of neurology | 2017 | PMID: 28444220 |
In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins. | Pakdaman Y | Bioscience reports | 2017 | PMID: 28396517 |
STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations. | Hayer SN | Orphanet journal of rare diseases | 2017 | PMID: 28193273 |
Optimization of laccase production from Marasmiellus palmivorus LA1 by Taguchi method of Design of experiments. | Chenthamarakshan A | BMC biotechnology | 2017 | PMID: 28193272 |
Autosomal recessive cerebellar ataxia of adult onset due to STUB1 mutations. | Depondt C | Neurology | 2014 | PMID: 24719489 |
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Text-mined citations for rs146251364 ...
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.