ClinVar Genomic variation as it relates to human health
NM_000429.3(MAT1A):c.791G>A (p.Arg264His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000429.3(MAT1A):c.791G>A (p.Arg264His)
Variation ID: 1208 Accession: VCV000001208.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q22.3 10: 80275177 (GRCh38) [ NCBI UCSC ] 10: 82034933 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 9, 2017 Jun 17, 2024 Jan 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000429.3:c.791G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000420.1:p.Arg264His missense NC_000010.11:g.80275177C>T NC_000010.10:g.82034933C>T NG_008083.1:g.19502G>A Q00266:p.Arg264His - Protein change
- R264H
- Other names
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- Canonical SPDI
- NC_000010.11:80275176:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MAT1A | - | - |
GRCh38 GRCh37 |
312 | 400 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 6, 2024 | RCV000001267.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2021 | RCV000413727.19 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hepatic methionine adenosyltransferase deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003823501.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hepatic methionine adenosyltransferase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000756279.8
First in ClinVar: Apr 21, 2017 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Jan 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001502621.19
First in ClinVar: Mar 14, 2021 Last updated: Jun 17, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490609.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 01, 1997)
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no assertion criteria provided
Method: literature only
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METHIONINE ADENOSYLTRANSFERASE I/III DEFICIENCY, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021417.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017 |
Comment on evidence:
In affected members of 2 unrelated families with MAT deficiency (250850) inherited in an autosomal dominant pattern (Blom et al., 1992; Mudd et al., 1995), … (more)
In affected members of 2 unrelated families with MAT deficiency (250850) inherited in an autosomal dominant pattern (Blom et al., 1992; Mudd et al., 1995), Chamberlin et al. (1997) identified a heterozygous 791G-A transition in the MAT1A gene, resulting in an arg264-to-his (R264H) substitution. In vitro studies suggested that residue 264 is involved in salt bridge formation essential for subunit dimerization and that the dominant effect of the R264H mutation is exerted by the formation of enzymatically inactive R264/R264H dimers. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hepatic methionine adenosyltransferase deficiency
Affected status: yes
Allele origin:
germline
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Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital
Accession: SCV004800851.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
PS3+PS4+PM2_P+PP1_S+PP3+PP4
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Han
Geographic origin: China
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Newborn Screening for Homocystinuria Revealed a High Frequency of MAT I/III Deficiency in Iberian Peninsula. | Marcão A | JIMD reports | 2015 | PMID: 25638462 |
Thirteen Patients with MAT1A Mutations Detected Through Newborn Screening: 13 Years' Experience. | Chadwick S | JIMD reports | 2014 | PMID: 24445979 |
Insight into S-adenosylmethionine biosynthesis from the crystal structures of the human methionine adenosyltransferase catalytic and regulatory subunits. | Shafqat N | The Biochemical journal | 2013 | PMID: 23425511 |
Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands. | Martins E | JIMD reports | 2012 | PMID: 23430947 |
Hypermethioninaemia due to methionine adenosyltransferase I/III (MAT I/III) deficiency: diagnosis in an expanded neonatal screening programme. | Couce ML | Journal of inherited metabolic disease | 2008 | PMID: 18500573 |
Biochemical basis for the dominant inheritance of hypermethioninemia associated with the R264H mutation of the MAT1A gene. A monomeric methionine adenosyltransferase with tripolyphosphatase activity. | Pérez Mato I | The Journal of biological chemistry | 2001 | PMID: 11278456 |
Dominant inheritance of isolated hypermethioninemia is associated with a mutation in the human methionine adenosyltransferase 1A gene. | Chamberlin ME | American journal of human genetics | 1997 | PMID: 9042912 |
Isolated persistent hypermethioninemia. | Mudd SH | American journal of human genetics | 1995 | PMID: 7573050 |
Persistent hypermethioninaemia with dominant inheritance. | Blom HJ | Journal of inherited metabolic disease | 1992 | PMID: 1527987 |
Text-mined citations for rs72558181 ...
HelpRecord last updated Jun 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.