Submissions for variant NM_003334.4(UBA1):c.121A>C (p.Met41Leu)

dbSNP: rs1936307795

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Tan Tock Seng Hospital, National Healthcare Group	RCV001265108	SCV001450457	pathogenic	VEXAS syndrome	2020-12-11	criteria provided, single submitter	clinical testing	This sequence alteration replaces methionine with leucine at codon 41 of the UBA1 gene (p.Met41Leu). This variant is absent in gnomAD and the alternative variant, Met41Val was reported in individuals with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (PMID: 33108101). The functional study showed that the missense change at codon 41 favors the production of the functionally defective cytoplasmic UBA1 isoform that results in the loss of ubiquitylation, and dysregulation of autophagy, leading to severe inflammatory conditions. For these reasons, this variant is classified as pathogenic.
Invitae	RCV001366437	SCV001562738	uncertain significance	Infantile-onset X-linked spinal muscular atrophy	2023-08-07	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 981654). This variant has been reported as a recurrent somatic variant in individuals with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (PMID: 33108101, 34048852), but has not been reported as a germline variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 41 of the UBA1 protein (p.Met41Leu). 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. Experimental studies have shown that this missense change affects UBA1 function (PMID: 33108101).
CeGaT Center for Human Genetics Tuebingen	RCV001815527	SCV002063311	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	UBA1: PM1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting
GeneDx	RCV001815527	SCV002097501	pathogenic	not provided	2022-04-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate disrupted cytoplasmic protein function and promotion of pro-inflammatory gene expression (Beck et al., 2020); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33630036, 26432019, 33690815, 34427584, 34480172, 33789873, 33108101)
MGZ Medical Genetics Center	RCV001265108	SCV002579909	likely pathogenic	VEXAS syndrome	2022-05-04	criteria provided, single submitter	clinical testing
Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine	RCV001265108	SCV003837569	pathogenic	VEXAS syndrome	2023-01-03	criteria provided, single submitter	clinical testing
Inflammatory Disease Section/Clinical Genetics Service, National Human Genome Research Institute	RCV001261201	SCV001438044	pathogenic	VEXAS	2020-10-01	no assertion criteria provided	research
OMIM	RCV001265108	SCV001443138	pathogenic	VEXAS syndrome	2023-02-06	no assertion criteria provided	literature only