ClinVar Genomic variation as it relates to human health
NM_030773.4(TUBB1):c.35del (p.Cys12fs)
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(2); Likely pathogenic(1); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_030773.4(TUBB1):c.35del (p.Cys12fs)
Variation ID: 586966 Accession: VCV000586966.14
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 20q13.32 20: 59019557 (GRCh38) [ NCBI UCSC ] 20: 57594612 (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 21, 2018 Apr 15, 2024 Feb 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_030773.4:c.35del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_110400.1:p.Cys12fs frameshift NM_030773.4:c.35delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_030773.3:c.35delG NP_110400.1:p.Cys12Leufs frameshift NC_000020.11:g.59019557del NC_000020.10:g.57594612del NG_023424.2:g.5304del LRG_581:g.5304del LRG_581t1:c.35del - Protein change
- C12fs
- Other names
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- Canonical SPDI
- NC_000020.11:59019556:G:
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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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TUBB1 | - | - |
GRCh38 GRCh37 |
214 | 232 |
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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Oct 18, 2016 | RCV000714242.1 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Feb 14, 2024 | RCV002222613.10 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 20, 2022 | RCV002293476.5 | |
TUBB1-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Oct 6, 2022 | RCV003420272.4 |
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
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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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Macrothrombocytopenia, isolated, 1, autosomal dominant
Affected status: yes
Allele origin:
germline
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002500914.2
First in ClinVar: Apr 23, 2022 Last updated: Sep 10, 2022
Comment:
Submitted to GoldVariant by Jose María Bastida and José Rivera; Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC)
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Observation 1:
Clinical Features:
Macrothrombocytopenia (present)
Family history: yes
Sex: male
Observation 2:
Clinical Features:
Macrothrombocytopenia (present)
Family history: yes
Sex: male
Observation 3:
Clinical Features:
Macrothrombocytopenia (present)
Family history: no
Sex: female
Observation 4:
Clinical Features:
Macrothrombocytopenia (present)
Family history: no
Sex: female
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Likely pathogenic
(Oct 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002586623.2
First in ClinVar: Oct 29, 2022 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29333906, 30446499, 31589614, 34662886, 34516618, 28983057, 32757236) (less)
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Uncertain significance
(Apr 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Macrothrombocytopenia, isolated, 1, autosomal dominant
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002519923.2
First in ClinVar: May 28, 2022 Last updated: Apr 15, 2023 |
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Uncertain significance
(Oct 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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TUBB1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004117299.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TUBB1 c.35delG variant is predicted to result in a frameshift and premature protein termination (p.Cys12Leufs*12). This variant has been reported in an individual with … (more)
The TUBB1 c.35delG variant is predicted to result in a frameshift and premature protein termination (p.Cys12Leufs*12). This variant has been reported in an individual with thyroid dysgenesis, and the variant was inherited from a parent with mild thyroid asymmetry but with normal thyroid function (Stoupa et al. 2018. PubMed ID: 30446499). This variant has also been reported in an individual with an inherited platelet disorder (Bastida et al. 2018. PubMed ID: 28983057) and an individual with nonsyndromic thrombocytopenia (Guéguen et al. 2020. PubMed ID: 32757236). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-57594611-TG-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Oct 20, 2022)
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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: SCV003271425.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. ClinVar contains an entry for this variant (Variation ID: 586966). This premature translational stop signal has been observed in individual(s) with thrombocytopenia and/or TUBB1-related macrothrombocytopenia (PMID: 28983057, 30446499, 32757236). This variant is present in population databases (rs773248042, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Cys12Leufs*12) in the TUBB1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TUBB1 cause disease. (less)
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Pathogenic
(Feb 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Macrothrombocytopenia, isolated, 1, autosomal dominant
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813279.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: TUBB1 c.35delG (p.Cys12LeufsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: TUBB1 c.35delG (p.Cys12LeufsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 251248 control chromosomes (gnomAD). c.35delG has been reported in the literature in individuals affected with congenital hypothyroidism or inherited platelet disorders (Stoupa_2018, Bastida_2018). These data indicate that the variant may be associated with disease. 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: 34662886, 28983057, 32757236, 30446499). ClinVar contains an entry for this variant (Variation ID: 586966). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 18, 2016)
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no assertion criteria provided
Method: research
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Congenital hypothyroidism
Affected status: yes
Allele origin:
germline
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Polak associated Lab, IMAGINE Institute
Accession: SCV000840555.1
First in ClinVar: Oct 21, 2018 Last updated: Oct 21, 2018 |
Number of individuals with the variant: 11
Geographic origin: European
Testing laboratory: Polak associated Lab,IMAGINE Institute
Date variant was reported to submitter: 2016-10-18
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Pathogenic
(Jul 07, 2022)
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no assertion criteria provided
Method: research
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Macrothrombocytopenia, isolated, 1, autosomal dominant
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
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Unidade de Genética Molecular, Centro Hospitalar Universitário do Porto
Accession: SCV002540770.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
Comment:
Variant identified in homozygosity in two of five affected members in the same family. PVS1, PP5, PP1
Indication for testing: Macrothrombocytopenia
Sex: female
Geographic origin: Portugal
Comment on evidence:
This variant was already reported in heterozygous cases
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Pathogenic
(Oct 12, 2023)
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no assertion criteria provided
Method: literature only
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MACROTHROMBOCYTOPENIA, ISOLATED, 1, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV004042667.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment on evidence:
In 4 patients from 2 unrelated Spanish families, 3 from pedigree A and 1 from pedigree B, with autosomal dominant isolated macrothrombocytopenia-1 (MACTHC1; 613112), Palma-Barqueros … (more)
In 4 patients from 2 unrelated Spanish families, 3 from pedigree A and 1 from pedigree B, with autosomal dominant isolated macrothrombocytopenia-1 (MACTHC1; 613112), Palma-Barqueros et al. (2021) identified heterozygosity for a 1-bp deletion (c.35del) in the TUBB1 gene predicted to result in frameshift and premature termination of the protein (Cys12LeufsTer12). The mutation was identified by sequencing of an inherited platelet disorder-associated gene panel consisting of 89 genes and confirmed by Sanger sequencing. The mutation was present in gnomAD with an allele frequency of 0.0000318 in the general population. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Unknown function
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Unidade de Genética Molecular, Centro Hospitalar Universitário do Porto
Accession: SCV002540770.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Exome sequencing and analysis of 454,787 UK Biobank participants. | Backman JD | Nature | 2021 | PMID: 34662886 |
Expanding the genetic spectrum of TUBB1-related thrombocytopenia. | Palma-Barqueros V | Blood advances | 2021 | PMID: 34516618 |
Pathogenic and likely pathogenic variants in at least five genes account for approximately 3% of mild isolated nonsyndromic thrombocytopenia. | Guéguen P | Transfusion | 2020 | PMID: 32757236 |
TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology. | Stoupa A | EMBO molecular medicine | 2018 | PMID: 30446499 |
Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders. | Bastida JM | Haematologica | 2018 | PMID: 28983057 |
Text-mined citations for rs773248042 ...
HelpRecord last updated May 27, 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.