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

dbSNP: rs1936307795

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001038219	SCV001201682	uncertain significance	Infantile-onset X-linked spinal muscular atrophy	2023-10-05	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV002255173	SCV002526469	pathogenic	not provided	2022-02-09	criteria provided, single submitter	clinical testing	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)
MGZ Medical Genetics Center	RCV001265106	SCV002580974	likely pathogenic	VEXAS syndrome	2022-06-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002363560	SCV002660885	pathogenic	Inborn genetic diseases	2022-02-09	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV002255173	SCV003917780	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	UBA1: PM1:Strong, PS2, PM2, PP4:Moderate
Johns Hopkins Genomics, Johns Hopkins University	RCV001265106	SCV003927238	pathogenic	VEXAS syndrome	2023-03-13	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV003411963	SCV004112945	pathogenic	UBA1-related disorder	2023-05-10	criteria provided, single submitter	clinical testing	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.
Inflammatory Disease Section/Clinical Genetics Service, National Human Genome Research Institute	RCV001261200	SCV001438043	pathogenic	VEXAS	2020-10-01	no assertion criteria provided	research
OMIM	RCV001265106	SCV001443136	pathogenic	VEXAS syndrome	2023-02-06	no assertion criteria provided	literature only
Undiagnosed Diseases Network, NIH	RCV001265106	SCV002098354	pathogenic	VEXAS syndrome	2022-08-03	no assertion criteria provided	clinical testing