Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000433867 | SCV000513537 | likely pathogenic | not provided | 2017-10-05 | criteria provided, single submitter | clinical testing | The P255S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P255S variant is not observed in large population cohorts (Lek et al., 2016). The P255S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, P255 is located in a region of the MAT1A protein (F250-A259) that is highly conserved and is believed to be involved in methionine positioning in the active site (, and multiple missense variants in nearby residues (I252T, G257R, D258G, A259V) have been reported in the Human Gene Mutation Database in association with methionine adenosyltransferase I/III (MAT I/III) deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret this variant as likely pathogenic. |
| Invitae | RCV001865323 | SCV002215328 | uncertain significance | Hepatic methionine adenosyltransferase deficiency | 2022-07-03 | criteria provided, single submitter | clinical testing | 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. 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: 378112). This missense change has been observed in individuals with clinical features of hypermethioninemia (PMID: 31061746). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 255 of the MAT1A protein (p.Pro255Ser). |