ClinVar Miner

Submissions for variant NM_000429.3(MAT1A):c.776C>T (p.Ala259Val) (rs138556525)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000540793 SCV000893845 pathogenic Hepatic methionine adenosyltransferase deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000376797 SCV000329412 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing The A259V missense variant has been reported previously in a patient with mildly elevated methionine levels on a normal diet in whom a second MAT1A variant was not identified by sequence analysis (Fernandez-Irigoyen et al., 2010). Expression studies found that A259V was associated with an approximately 80-95% reduction in methionine adenosyltransferase (MATI/III) activity compared with wild-type enzyme while tripolyphosphatase activity, the second step in the reaction catalyzed by MAT I/III enzyme, was only slightly reduced (Fernandez-Irigoyet et al., 2010). The region of the MAT1A protein from F250-A259 is highly conserved and has been proposed to be involved in methionine positioning at the active site (Fernandez-Irigoyet et al., 2010). The majority of MAT1A variants are inherited in an autosomal recessive manner; however, dominant inheritance has been well documented for a single R264H missense variant. At this time, there is not enough evidence to support A259V as a dominant variant (Fernandez-Irigoyet et al., 2010).
Invitae RCV000540793 SCV000631974 pathogenic Hepatic methionine adenosyltransferase deficiency 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 259 of the MAT1A protein (p.Ala259Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs138556525, ExAC 0.01%). This variant has been identified as heterozygous in individuals and a family with autosomal dominant hypermethioninemia (PMID: 20675163, 24445979, 28748147, Invitae). ClinVar contains an entry for this variant (Variation ID: 279845). Experimental studies have shown that this missense change causes a reduction in MAT enzymatic activity to less than 20% of the wild-type level (PMID: 20675163). Structural studies have shown that this variant resides in the dimer interface of the protein. Variants localized in this region or in the substrate binding site have been associated with the autosomal dominant form of disease due to their disruption of the dimerization of the protein or substrate binding, whereas the autosomal recessive variants are located elsewhere in the protein (PMID: 23425511, 26933843, 28748147). In summary, this variant is a rare missense change that has been reported in several affected individuals and it has been shown to have a deleterious impact on protein function. Therefore, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.