Submissions for variant NM_000429.3(MAT1A):c.529C>T (p.Arg177Trp)

gnomAD frequency: 0.00003  dbSNP: rs376757912

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489288	SCV000577527	likely pathogenic	not provided	2025-02-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26933843, 26289392, 24445979, 35760084, 31061746, 38380423, 28186605)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000634908	SCV000756278	pathogenic	Hepatic methionine adenosyltransferase deficiency	2024-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 177 of the MAT1A protein (p.Arg177Trp). This variant is present in population databases (rs376757912, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive hypermethioninemia (PMID: 24445979, 26289392, 28186605, 31061746; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 426944). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAT1A protein function. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003409676	SCV004114134	pathogenic	MAT1A-related disorder	2023-05-24	criteria provided, single submitter	clinical testing	The MAT1A c.529C>T variant is predicted to result in the amino acid substitution p.Arg177Trp. This variant has been reported in the homozygous or compound heterozygous state in individuals with hypermethioninemia (Chien et al 2015. PubMed ID: 26289392; Sun et al 2017. PubMed ID: 28186605; Zhao et al. 2022. PubMed ID: 35760084). It has also been reported in patients with abnormal newborn screen results (Chadwick et al 2014. PubMed ID: 24445979; Sen et al. 2019. PubMed ID: 31061746; Zhang et al. 2020. PubMed ID: 31851615). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-82039949-G-A). This variant is interpreted as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701545	SCV005202265	uncertain significance	not specified	2024-07-29	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000634908	SCV003808290	uncertain significance	Hepatic methionine adenosyltransferase deficiency	2022-08-01	flagged submission	clinical testing