Gene Validity Curation

MAT1A - brain demyelination due to methionine adenosyltransferase deficiency

Gene: MAT1A (HGNC:6903)
Classification - 09/13/2019
Disease: brain demyelination due to methionine adenosyltransferase deficiency (MONDO_0009607)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Aminoacidopathy EP
Evidence Summary: The relationship between MAT1A and methionine adenosyltransferase deficiency was evaluated using the ClinGen Clinical Validity Framework as of August 15th, 2019. Methionine adenosyltransferase catalyzes a two-step reaction in which the adenosyl group of ATP is transferred to methionine to form S-adenosylmethionine, a methyl donor, and tripolyphosphate. Individuals with methionine adenosyltransferase deficiency present with persistently elevated levels of plasma methionine. Most patients with this condition are identified with hypermethioninemia on newborn screening. Follow up testing reveals normal or mildly elevated homocysteine, ruling out homocystinuria, and normal tyrosine, ruling out tyrosinemia. Most individuals with methionine adenosyltransferase deficiency have no symptoms, although some patients have developed demyelination of the brain and other abnormalities (Nashabat et al, 2018, PMID 29440907). Biallelic variants in MAT1A causing methionine adenosyltransferase were first reported by Ubagai et al in 1995 (PMID 7560086). Data from 17 patients who are homozygous or compound heterozygous for MAT1A variants were curated, including 21 unique variants (missense, nonsense, frameshift, and splicing) from 8 publications (Ubagai et al, 1995, PMID 7560086; Chamberlin et al, 1996, PMID 8770875; Hazelwood et al, 1998, PMID 9482646; Linneback et al, 2005, PMID 16435220; Fernández-Irigoyen et al, 2010, PMID 20675163; Hirabayashi et al, 2013, PMID 23973726; Nagao et al, 2013, PMID 24231718; Kim et al, 2016, PMID 26933843). More data are available but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of methionine adenosyltransferase, which is consistent with the finding of persistently elevated methionine levels in patients with this condition (Cantoni, 1951, PMID 14832292; Mudd, 1962, PMID 14476836), and a knock out mouse model (Lu et al, 2001; PMID 11320206). In summary, MAT1A is definitively associated with autosomal recessive methionine adenosyltransferase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on September 13th, 2019. Of note, while most individuals who are heterozygous for variants causing autosomal recessive methionine adenosyltransferase deficiency have normal methionine levels, some variants are reported to cause hypermethioninemia in the heterozygous state, although the level of methionine is lower than that seen in individuals who have biallelic variants in MAT1A (Kim et al, 2016; PMID 26933843). The most commonly reported variant, c.791G>A (p.Arg264His), has been shown to segregate with hypermethioninemia is an autosomal dominant manner. This variant disrupts the normal dimerization of methionine adenosyltransferase and therefore appears to act as a dominant-negative (Chamberlin et al, 1997, PMID 9042912).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 7
8.5
12
Kim YM et al. 2016 Sep (PMID:26933843); Hazelwood S et al. 1998 Feb 3 (PMID:9482646); Chamberlin ME et al. 1996 Aug 15 (PMID:8770875); Nagao M et al. 2013 Dec (PMID:24231718); Hirabayashi K et al. 2013 Nov 1 (PMID:23973726);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 10
5.5
Ubagai T et al. 1995 Oct (PMID:7560086); Chamberlin ME et al. 1996 Aug 15 (PMID:8770875); Linnebank M et al. 2005 (PMID:16435220); Nagao M et al. 2013 Dec (PMID:24231718); Fernández-Irigoyen J et al. 2010 Oct-Nov (PMID:20675163);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 2
2
2
CANTONI GL et al. 1951 Apr (PMID:14832292); MUDD SH et al. 1962 Apr (PMID:14476836);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Lu SC et al. 2001 May 8 (PMID:11320206);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 4 16 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
05/08/2020
EXPERT CURATION (DATE)
Definitive
09/13/2019
EVIDENCE SUMMARY
The relationship between MAT1A and methionine adenosyltransferase deficiency was evaluated using the ClinGen Clinical Validity Framework as of August 15th, 2019. Methionine adenosyltransferase catalyzes a two-step reaction in which the adenosyl group of ATP is transferred to methionine to form S-adenosylmethionine, a methyl donor, and tripolyphosphate. Individuals with methionine adenosyltransferase deficiency present with persistently elevated levels of plasma methionine. Most patients with this condition are identified with hypermethioninemia on newborn screening. Follow up testing reveals normal or mildly elevated homocysteine, ruling out homocystinuria, and normal tyrosine, ruling out tyrosinemia. Most individuals with methionine adenosyltransferase deficiency have no symptoms, although some patients have developed demyelination of the brain and other abnormalities (Nashabat et al, 2018, PMID 29440907). Biallelic variants in MAT1A causing methionine adenosyltransferase were first reported by Ubagai et al in 1995 (PMID 7560086). Data from 17 patients who are homozygous or compound heterozygous for MAT1A variants were curated, including 21 unique variants (missense, nonsense, frameshift, and splicing) from 8 publications (Ubagai et al, 1995, PMID 7560086; Chamberlin et al, 1996, PMID 8770875; Hazelwood et al, 1998, PMID 9482646; Linneback et al, 2005, PMID 16435220; Fernández-Irigoyen et al, 2010, PMID 20675163; Hirabayashi et al, 2013, PMID 23973726; Nagao et al, 2013, PMID 24231718; Kim et al, 2016, PMID 26933843). More data are available but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of methionine adenosyltransferase, which is consistent with the finding of persistently elevated methionine levels in patients with this condition (Cantoni, 1951, PMID 14832292; Mudd, 1962, PMID 14476836), and a knock out mouse model (Lu et al, 2001; PMID 11320206). In summary, MAT1A is definitively associated with autosomal recessive methionine adenosyltransferase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on September 13th, 2019. Of note, while most individuals who are heterozygous for variants causing autosomal recessive methionine adenosyltransferase deficiency have normal methionine levels, some variants are reported to cause hypermethioninemia in the heterozygous state, although the level of methionine is lower than that seen in individuals who have biallelic variants in MAT1A (Kim et al, 2016; PMID 26933843). The most commonly reported variant, c.791G>A (p.Arg264His), has been shown to segregate with hypermethioninemia is an autosomal dominant manner. This variant disrupts the normal dimerization of methionine adenosyltransferase and therefore appears to act as a dominant-negative (Chamberlin et al, 1997, PMID 9042912).