Submissions for variant NM_000429.3(MAT1A):c.791G>A (p.Arg264His)

dbSNP: rs72558181

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413727	SCV000490609	pathogenic	not provided	2018-01-09	criteria provided, single submitter	clinical testing	The R264H missense variant in the MAT1A gene has been reported in association with autosomal dominant inheritance of methionine adenosyltransferase I/III (MAT I/III) deficiency (Chamberlin et al., 1997; Chamberlin et al., 2000; Couce et al., 2008; Chien et al., 2005). Amino acid 264 in the methionine adenosyltransferase (MAT) alpha-1 subunit is reported to be involved in salt-bridge formation that is essential for subunit dimerization. R264/R264H MAT alpha-1 heterodimers are enzymatically inactive; therefore, R264H has a dominant negative effect on the MAT enzyme (Chamberlin et al., 1997). Most individuals with MAT I/III deficiency, particularly those with the R264H subsitution, have elevation of plasma methionine and a relatively benign course, although the elevated methionine may be associated with an unusual breath odor. Therefore, we interpret R264H as a pathogenic variant.
Invitae	RCV000001267	SCV000756279	pathogenic	Hepatic methionine adenosyltransferase deficiency	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 264 of the MAT1A protein (p.Arg264His). 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 missense change has been observed in individuals with autosomal dominant hypermethioninemia (PMID: 9042912, 18500573, 23430947, 24445979, 25638462). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1208). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAT1A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MAT1A function (PMID: 9042912, 11278456, 23425511). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000413727	SCV001502621	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000001267	SCV003823501	pathogenic	Hepatic methionine adenosyltransferase deficiency	2023-05-31	criteria provided, single submitter	clinical testing
OMIM	RCV000001267	SCV000021417	pathogenic	Hepatic methionine adenosyltransferase deficiency	1997-03-01	no assertion criteria provided	literature only
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000001267	SCV004800851	pathogenic	Hepatic methionine adenosyltransferase deficiency		no assertion criteria provided	clinical testing	PS3+PS4+PM2_P+PP1_S+PP3+PP4