ClinVar Genomic variation as it relates to human health
NM_003334.4(UBA1):c.122T>C (p.Met41Thr)
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(5); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003334.4(UBA1):c.122T>C (p.Met41Thr)
Variation ID: 965290 Accession: VCV000965290.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.3 X: 47199052 (GRCh38) [ NCBI UCSC ] X: 47058451 (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 Jul 16, 2020 Apr 15, 2024 Nov 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003334.4:c.122T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003325.2:p.Met41Thr missense NM_153280.3:c.122T>C NP_695012.1:p.Met41Thr missense NC_000023.11:g.47199052T>C NC_000023.10:g.47058451T>C NG_009161.1:g.13253T>C - Protein change
- M41T
- Other names
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- Canonical SPDI
- NC_000023.11:47199051:T: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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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LOC126863253 | - | - | - | GRCh38 | - | 138 |
UBA1 | - | - |
GRCh38 GRCh37 |
504 | 722 |
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
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
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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) |
criteria provided, single submitter
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Nov 8, 2023 | RCV001239702.6 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 1, 2020 | RCV001261202.2 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 3, 2022 | RCV001265107.10 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV001702587.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 9, 2023 | RCV003405435.4 |
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
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
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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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VEXAS syndrome
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002558040.1
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 Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with infantile spinal muscular atrophy (MIM#301830) and VEXAS syndrome (MIM#301054). (I) 0109 - This gene is associated with X-linked recessive disease infantile spinal muscular atrophy (MIM#301830) and the somatically acquired VEXAS syndrome (MIM#301054). Variants associated with the germline condition tend to cluster within exon 15 while those associated with the somatic condition predominantly affect Met41 (GeneReviews, PMID: 33108101, 33690815). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to threonine. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least fifteen individuals with VEXAS syndrome (PMID: 33108101). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Jun 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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VEXAS syndrome
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580104.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 2
Sex: male
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Pathogenic
(Jan 04, 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: SCV002513015.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that variants altering the M41 codon disrupted translation and production of the cytoplasmic isoform, leading to the upregulation of pro-inflammatory gene … (more)
Published functional studies demonstrate that variants altering the M41 codon disrupted translation and production of the cytoplasmic isoform, leading to the upregulation of pro-inflammatory gene expression (Beck et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 33779074, 33108101, 33690815, 33789873, 34427584, 34632574) (less)
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Pathogenic
(Nov 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026198.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PS4, PM2_SUP
Observation 1: Observation 2: Observation 3: |
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Pathogenic
(Mar 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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UBA1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004106351.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The UBA1 c.122T>C variant is predicted to result in the amino acid substitution p.Met41Thr. This variant has been reported as a post-zygotic mosaic substitution in … (more)
The UBA1 c.122T>C variant is predicted to result in the amino acid substitution p.Met41Thr. This variant has been reported as a post-zygotic mosaic substitution in multiple individuals with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. The majority of reported patients harbored mosaic variants affecting this residue (p.Met41Val, pMet41Thr, p.Met41Leu) (Beck et al. 2020. PubMed ID: 33108101; Poulter et al. 2021. PubMed ID: 33690815). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants altering p.Met41 result in the loss of a canonical isoform and expression of a catalytically impaired isoform of UBA1 (Beck et al. 2020. PubMed ID: 33108101). This variant is interpreted as pathogenic. (less)
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Uncertain significance
(Nov 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Infantile-onset X-linked spinal muscular atrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001412595.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 41 of the UBA1 protein (p.Met41Thr). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 41 of the UBA1 protein (p.Met41Thr). This variant is not present in population databases (gnomAD no frequency). This variant has been reported as a recurrent somatic variant in individuals with a late-onset, treatment refractory inflammatory syndrome (PMID: 33108101), but has not been reported as a germline variant. ClinVar contains an entry for this variant (Variation ID: 965290). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects UBA1 function (PMID: 33108101). 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
(Aug 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001962623.14
First in ClinVar: Oct 10, 2021 Last updated: Apr 15, 2024 |
Comment:
UBA1: PVS1, PM2, PS4:Moderate, PP4, PS3:Supporting
Number of individuals with the variant: 8
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Pathogenic
(Oct 01, 2020)
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no assertion criteria provided
Method: research
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VEXAS
Affected status: yes
Allele origin:
somatic
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Inflammatory Disease Section/Clinical Genetics Service, National Human Genome Research Institute
Accession: SCV001438045.1
First in ClinVar: Oct 23, 2020 Last updated: Oct 23, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927509.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953361.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963240.1 First in ClinVar: Oct 10, 2021 Last updated: Oct 10, 2021 |
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Pathogenic
(Feb 06, 2023)
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no assertion criteria provided
Method: literature only
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VEXAS SYNDROME, SOMATIC
Affected status: not provided
Allele origin:
somatic
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OMIM
Accession: SCV001443137.5
First in ClinVar: Nov 19, 2020 Last updated: Mar 18, 2023 |
Comment on evidence:
In 15 unrelated men with VEXAS syndrome (VEXAS; 301054), Beck et al. (2020) identified a somatic c.122T-C transition (c.122T-C, NM_003334.3) in the UBA1 gene, resulting … (more)
In 15 unrelated men with VEXAS syndrome (VEXAS; 301054), Beck et al. (2020) identified a somatic c.122T-C transition (c.122T-C, NM_003334.3) in the UBA1 gene, resulting in a met41-to-thr (M41T) substitution at the translation initiation site for the cytoplasmic UBA1b isoform. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant into HEK293T cells resulted in loss of UBA1b and the presence of a shortened isoform, designated UBA1c, that was initiated from a Met67 codon. UBA1c localized to the cytoplasm. In vitro functional expression studies showed that the UBA1c isoform was catalytically impaired compared to UBA1a and UBA1b, consistent with a loss of function. By Sanger sequencing of the UBA1 gene in 5 unrelated men with VEXAS, Poulter et al. (2021) identified a somatic M41T substitution. In 7 of 12 patients with VEXAS syndrome, van der Made et al. (2022) identified a somatic M41T mutation in the UBA1 gene. Variant Function Through detailed in vitro studies of the M41T mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, Ferrada et al. (2022) demonstrated that it resulted in decreased levels of UBA1b, indicating impaired translation of the isoform. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and may affect disease prognosis. (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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Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. | Ferrada MA | Blood | 2022 | PMID: 35793467 |
Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS. | van der Made CI | The Journal of allergy and clinical immunology | 2022 | PMID: 34048852 |
Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. | Poulter JA | Blood | 2021 | PMID: 33690815 |
Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. | Beck DB | The New England journal of medicine | 2020 | PMID: 33108101 |
Text-mined citations for rs782416867 ...
HelpRecord last updated Apr 15, 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.