VCV000836983.38 - ClinVar

NM_003334.4(UBA1):c.121A>G (p.Met41Val)

Germline

Classification

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.

(10)

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.

Conflicting classifications of pathogenicity
Pathogenic(5); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003334.4(UBA1):c.121A>G (p.Met41Val)

Variation ID: 836983 Accession: VCV000836983.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp11.3 X: 47199051 (GRCh38) [ NCBI UCSC ] X: 47058450 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 15, 2020	Oct 20, 2024	Oct 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003334.4:c.121A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003325.2:p.Met41Val	missense
NM_153280.3:c.121A>G	NP_695012.1:p.Met41Val	missense
NC_000023.11:g.47199051A>G
NC_000023.10:g.47058450A>G
NG_009161.1:g.13252A>G

... more HGVS ... less HGVS

Protein change

M41V

Other names

p.M41V
p.Met41Val

Canonical SPDI

NC_000023.11:47199050:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 314370.0004 dbSNP: rs1936307795 VarSome

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
Gene	OMIM	HI score Help 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.
LOC126863253	-	-	-	GRCh38	-	140
UBA1		-	-	GRCh38 GRCh37	512	733

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.
Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (1)	criteria provided, single submitter	Oct 5, 2023	RCV001038219.10
VEXAS syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 13, 2023	RCV001265106.13
VEXAS	Pathogenic (1)	no assertion criteria provided	Oct 1, 2020	RCV001261200.2
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Feb 9, 2022	RCV002363560.3
UBA1-related disorder	Pathogenic (1)	criteria provided, single submitter	May 10, 2023	RCV003411963.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 1, 2023	RCV002255173.15

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.
Likely pathogenic (Jun 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	VEXAS syndrome Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580974.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3_MOD, PS4_MOD, PM5, PM2_SUP, PP4	Number of individuals with the variant: 1 Sex: male
Pathogenic (Feb 09, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002526469.2 First in ClinVar: Jun 24, 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 in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 33881233, 33779074, 33789873, 33690815, 33108101, 27535533) (less)
Pathogenic (Mar 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	VEXAS syndrome Affected status: unknown Allele origin: somatic	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV003927238.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (5) PubMed: 33108101‚ 34048852‚ 35793467‚ 36038944‚ 36662445 Comment: This UBA1 variant (rs1936307795) is absent from a large population dataset and has been reported in ClinVar. This variant has been reported as a somatic … (more) This UBA1 variant (rs1936307795) is absent from a large population dataset and has been reported in ClinVar. This variant has been reported as a somatic alteration in several unrelated individuals with VEXAS syndrome. Two other alterations at the same codon, p.Met41Leu and p.Met41Thr, have also been reported as somatic variants in individuals with VEXAS syndrome. Experimental studies in HEK293 cells and patient monocytes demonstrated a loss of the cytoplasmic protein isoform (UBA1b) and upregulation of pro-inflammatory gene expression. Bioinformatic analysis predicts that this missense variant would not affect normal exon 3 splicing, although this has not been confirmed experimentally to our knowledge. High variant allele fraction (VAF) for VEXAS-associated somatic UBA1 variants has been reported. We consider c.121A>G (p.Met41Val) to be pathogenic for VEXAS syndrome. (less)
Pathogenic (May 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	UBA1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004112945.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The UBA1 c.121A>G variant is predicted to result in the amino acid substitution p.Met41Val. This variant has been reported as a post-zygotic mosaic substitution in … (more) The UBA1 c.121A>G variant is predicted to result in the amino acid substitution p.Met41Val. This variant has been reported as a post-zygotic mosaic substitution in multiple individuals with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, and the majority of reported patients have 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). The c.121A>G (p.Met41Val) variant is absent from a large general population database, indicating it is rare (http://gnomad.broadinstitute.org). This variant is classified as pathogenic for somatic VEXAS syndrome; however, the classification of this variant related to infantile spinal muscular atrophy is uncertain at this time due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Oct 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Infantile-onset X-linked spinal muscular atrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001201682.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 33108101‚ 33789873 Comment: This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 41 of the UBA1 protein (p.Met41Val). … (more) This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 41 of the UBA1 protein (p.Met41Val). This variant is not present in population databases (gnomAD no frequency). This variant has been reported as a recurrent somatic variant in individuals with VEXAS syndrome (PMID: 33108101, 33789873), but has not been reported as a germline variant. ClinVar contains an entry for this variant (Variation ID: 836983). 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)
Pathogenic (Feb 09, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002660885.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 33108101‚ 34647982‚ 34649277 Comment: The p.M41V pathogenic mutation (also known as c.121A>G), located in coding exon 2 of the UBA1 gene, results from an A to G substitution at … (more) The p.M41V pathogenic mutation (also known as c.121A>G), located in coding exon 2 of the UBA1 gene, results from an A to G substitution at nucleotide position 121. The methionine at codon 41 is replaced by valine, an amino acid with highly similar properties. This variant has been reported to occur as a somatic alteration in several men with VEXAS syndrome (Beck DB et al. N Engl J Med, 2020 12;383:2628-2638; Horton RK et al. Blood, 2021 10;138:1378; Li P et al. Blood Adv, 2022 Jan;6:405-409). HEK293 cells, as well as monocytes from an affected male, demonstrated a loss of the UBA1b transcript and a new transcript, UBA1c, due to an alternate initiation site at codon 67 (Beck DB et al. N Engl J Med, 2020 12;383:2628-2638). This amino acid position is highly conserved in available vertebrate species. Two other alterations at the same codon, p.Met41Leu (c.121A>C) and p.Met41Thr (c.122T>C), have also been reported as somatic variants in individuals with VEXAS syndrome (Beck DB et al. N Engl J Med, 2020 12;383:2628-2638; Li P et al. Blood Adv, 2022 Jan;6:405-409). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of VEXAS syndrome; however, its clinical significance for UBA1-related X-linked infantile spinal muscular atrophy is unclear. (less)
Pathogenic (Jan 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003917780.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: UBA1: PM1:Strong, PS2, PM2, PP4:Moderate Number of individuals with the variant: 1
Pathogenic (Oct 01, 2020)	no assertion criteria provided Method: research	VEXAS Affected status: yes Allele origin: somatic	Inflammatory Disease Section/Clinical Genetics Service, National Human Genome Research Institute Accession: SCV001438043.1 First in ClinVar: Oct 23, 2020 Last updated: Oct 23, 2020
Pathogenic (Feb 06, 2023)	no assertion criteria provided Method: literature only	VEXAS SYNDROME, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV001443136.5 First in ClinVar: Nov 19, 2020 Last updated: Mar 18, 2023	Publications: PubMed (4) PubMed: 33108101‚ 33690815‚ 34048852‚ 35793467 Comment on evidence: In 5 unrelated men with VEXAS syndrome (VEXAS; 301054), Beck et al. (2020) identified a somatic c.121A-G transition (c.121A-G, NM_003334.3) in the UBA1 gene, resulting … (more) In 5 unrelated men with VEXAS syndrome (VEXAS; 301054), Beck et al. (2020) identified a somatic c.121A-G transition (c.121A-G, NM_003334.3) in the UBA1 gene, resulting in a met41-to-val (M41V) 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 3 unrelated men with VEXAS, Poulter et al. (2021) identified a somatic M41V substitution. In 4 of 12 patients with VEXAS syndrome, van der Made et al. (2022) identified a somatic M41V mutation in the UBA1 gene. Variant Function Through detailed in vitro studies of the M41V mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, Ferrada et al. (2022) demonstrated that it resulted in decreased levels of UBA1b, about 2-fold lower than M41L or M41T. These findings indicated that M41V does not support translation of UBA1b as well as the other variants, and showed that VEXAS syndrome severity inversely correlates with residual UBA1b levels. 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 affects disease prognosis. (less)
Pathogenic (Aug 03, 2022)	no assertion criteria provided Method: clinical testing	VEXAS syndrome Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV002098354.2 First in ClinVar: Feb 26, 2022 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 33108101 Number of individuals with the variant: 1 Clinical Features: Subcutaneous nodule (present) , Thrombocytopenia (present) , Abnormal granulocyte morphology (present) , Fever (present) , Macrocytic anemia (present) , Arthralgia (present) , Increased circulating ferritin … (more) Subcutaneous nodule (present) , Thrombocytopenia (present) , Abnormal granulocyte morphology (present) , Fever (present) , Macrocytic anemia (present) , Arthralgia (present) , Increased circulating ferritin concentration (present) , Elevated erythrocyte sedimentation rate (present) , Inflammatory abnormality of the skin (present) , Anisocytosis (present) , Abnormality of T cell physiology (present) , Single lineage myelodysplasia (present) , Monocytosis (present) , Erythematous plaque (present) , Night sweats (present) , Bone marrow hypercellularity (present) , Angioedema (present) (less) Age: 60-69 years Sex: male Tissue: Blood

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 expression (Beck et al., 2020); Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 33881233, 33779074, 33789873, 33690815, 33108101, 27535533)

Comment:

This UBA1 variant (rs1936307795) is absent from a large population dataset and has been reported in ClinVar. This variant has been reported as a somatic alteration in several unrelated individuals with VEXAS syndrome. Two other alterations at the same codon, p.Met41Leu and p.Met41Thr, have also been reported as somatic variants in individuals with VEXAS syndrome. Experimental studies in HEK293 cells and patient monocytes demonstrated a loss of the cytoplasmic protein isoform (UBA1b) and upregulation of pro-inflammatory gene expression. Bioinformatic analysis predicts that this missense variant would not affect normal exon 3 splicing, although this has not been confirmed experimentally to our knowledge. High variant allele fraction (VAF) for VEXAS-associated somatic UBA1 variants has been reported. We consider c.121A>G (p.Met41Val) to be pathogenic for VEXAS syndrome.

Comment:

The UBA1 c.121A>G variant is predicted to result in the amino acid substitution p.Met41Val. This variant has been reported as a post-zygotic mosaic substitution in multiple individuals with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, and the majority of reported patients have 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). The c.121A>G (p.Met41Val) variant is absent from a large general population database, indicating it is rare (http://gnomad.broadinstitute.org). This variant is classified as pathogenic for somatic VEXAS syndrome; however, the classification of this variant related to infantile spinal muscular atrophy is uncertain at this time due to the absence of conclusive functional and genetic evidence.

Comment:

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 41 of the UBA1 protein (p.Met41Val). This variant is not present in population databases (gnomAD no frequency). This variant has been reported as a recurrent somatic variant in individuals with VEXAS syndrome (PMID: 33108101, 33789873), but has not been reported as a germline variant. ClinVar contains an entry for this variant (Variation ID: 836983). 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.

Comment:

The p.M41V pathogenic mutation (also known as c.121A>G), located in coding exon 2 of the UBA1 gene, results from an A to G substitution at nucleotide position 121. The methionine at codon 41 is replaced by valine, an amino acid with highly similar properties. This variant has been reported to occur as a somatic alteration in several men with VEXAS syndrome (Beck DB et al. N Engl J Med, 2020 12;383:2628-2638; Horton RK et al. Blood, 2021 10;138:1378; Li P et al. Blood Adv, 2022 Jan;6:405-409). HEK293 cells, as well as monocytes from an affected male, demonstrated a loss of the UBA1b transcript and a new transcript, UBA1c, due to an alternate initiation site at codon 67 (Beck DB et al. N Engl J Med, 2020 12;383:2628-2638). This amino acid position is highly conserved in available vertebrate species. Two other alterations at the same codon, p.Met41Leu (c.121A>C) and p.Met41Thr (c.122T>C), have also been reported as somatic variants in individuals with VEXAS syndrome (Beck DB et al. N Engl J Med, 2020 12;383:2628-2638; Li P et al. Blood Adv, 2022 Jan;6:405-409). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of VEXAS syndrome; however, its clinical significance for UBA1-related X-linked infantile spinal muscular atrophy is unclear.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
VEXAS syndrome: a new paradigm for adult-onset monogenic autoinflammatory diseases.	Vitale A	Internal and emergency medicine	2023	PMID: 36662445
Exome sequencing can misread high variant allele fraction of somatic variants in UBA1 as hemizygous in VEXAS syndrome: a case report.	Wilke MVMB	BMC rheumatology	2022	PMID: 36038944
Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.	Ferrada MA	Blood	2022	PMID: 35793467
A clinical, histopathological, and molecular study of two cases of VEXAS syndrome without a definitive myeloid neoplasm.	Li P	Blood advances	2022	PMID: 34649277
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
A case of VEXAS syndrome with subtle morphologic findings.	Horton RK	Blood	2021	PMID: 34647982
Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis.	Tsuchida N	Annals of the rheumatic diseases	2021	PMID: 33789873
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 rs1936307795 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_003334.4(UBA1):c.121A>G (p.Met41Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1936307795 ...