ClinVar

Description

Variant summary: MAT1A c.529C>T (p.Arg177Trp) results in a non-conservative amino acid change located in the S-adenosylmethionine synthetase, central domain (IPR022629) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251364 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MAT1A causing Hepatic methionine adenosyltransferase deficiency, allowing no conclusion about variant significance. c.529C>T has been reported in the literature as homozygous, compount heterozygous, or heterozygous genotype in individuals affected with hypermethioninemia without evidence of CNS abnormalities (Chadwick_2014, Chien_2015, Sen_2019, Sun_2017, Zhao_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hepatic methionine adenosyltransferase deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24445979, 26289392, 31061746, 28186605, 35760084). ClinVar contains an entry for this variant (Variation ID: 426944). Based on the evidence outlined above, the variant was classified as uncertain significance.