ClinVar Miner

Submissions for variant NM_000429.3(MAT1A):c.791G>A (p.Arg264His) (rs72558181)

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Total submissions: 3
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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 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 264 of the MAT1A protein (p.Arg264His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs72558181, ExAC 0.01%). This variant has been reported to segregate with hypermethioninemia in two families (PMID: 9042912). It has also been reported in unrelated individuals with this condition (PMID: 23430947, 24445979, 25638462, 18500573) and this variant is commonly found in the autosomal dominant form of this condition. ClinVar contains an entry for this variant (Variation ID: 1208). Experimental studies have shown that this missense change abrogates MAT1A enzyme activity (PMID: 9042912, 11278456, 23425511). A different missense substitution at this codon (p.Arg264Cys) has been determined to be pathogenic (PMID: 10677294, 26289392). This suggests that the arginine residue is critical for MAT1A protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001267 SCV000021417 pathogenic Hepatic methionine adenosyltransferase deficiency 1997-03-01 no assertion criteria provided literature only

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