Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000698221 | SCV000826873 | uncertain significance | Hepatic methionine adenosyltransferase deficiency | 2018-04-26 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with tryptophan at codon 249 of the MAT1A protein (p.Arg249Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs779094715, ExAC 0.04%). This variant has been reported as heterozygous in an individual affected with hypermethioninemia (PMID: 15935930). Experimental studies have shown that this missense change causes a reduction in MAT enzymatic activity to approximately 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 autosomal recessive variants are located elsewhere in the protein (PMID: 23425511, 26933843, 28748147). 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. |