Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481494 | SCV000566243 | pathogenic | not provided | 2016-06-03 | criteria provided, single submitter | clinical testing | The R299C missense variant in the MAT1A gene has been reported previously inassociation with methionine adenosyltransferase I/III (MAT I/III) deficiency in a patient whowas homozygous for this variant (Fernandez-Irigoyen et al., 2010). Functional studiesfound that R299C results in low activities of both methionine adenosyltransferase andtripolyphosphatase (Fernandez-Irigoyen et al., 2010). The R219H variant has not been published as apathogenic variant, nor has it been reported as a benign variant to our knowledge. The R219H variantis a conservative amino acid substitution, which is not likely to impact secondary protein structure asthese residues share similar properties. This substitution occurs at a position that is conserved inmammals. In silico analysis is inconsistent in its predictions as to whether or not the variant isdamaging to the protein structure/function. Therefore, we interpret R299C as a pathogenic variant. |
| Fulgent Genetics, |
RCV000763218 | SCV000893844 | pathogenic | Hepatic methionine adenosyltransferase deficiency | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000763218 | SCV003441575 | pathogenic | Hepatic methionine adenosyltransferase deficiency | 2022-03-18 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg299 amino acid residue in MAT1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20675163, 32496220). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MAT1A function (PMID: 20675163). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 418870). This missense change has been observed in individuals with autosomal recessive hypermethioninemia (PMID: 20675163, 26933843). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 299 of the MAT1A protein (p.Arg299Cys). |