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NM_005957.5(MTHFR):c.1286A>C (p.Glu429Ala)

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Interpretation:
Conflicting interpretations of pathogenicity; other​

Likely pathogenic(1); Uncertain significance(2); Benign(5)

Review status:
criteria provided, conflicting interpretations
Submissions:
18
First in ClinVar:
Nov 13, 2014
Most recent Submission:
Jul 9, 2022
Last evaluated:
Oct 21, 2021
Accession:
VCV000003521.67
Variation ID:
3521
Description:
single nucleotide variant
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NM_005957.5(MTHFR):c.1286A>C (p.Glu429Ala)

Allele ID
18560
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
1p36.22
Genomic location
1: 11794419 (GRCh38) GRCh38 UCSC
1: 11854476 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_005957.5:c.1286A>C MANE Select NP_005948.3:p.Glu429Ala missense
NM_001330358.2:c.1409A>C NP_001317287.1:p.Glu470Ala missense
NC_000001.11:g.11794419T>G
... more HGVS
Protein change
E470A
Other names
MTHFR, 1298A-C, GLU429ALA (rs1801131)
E429A
Canonical SPDI
NC_000001.11:11794418:T:G
Functional consequence
-
Global minor allele frequency (GMAF)
0.24940 (G)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.24909
The Genome Aggregation Database (gnomAD) 0.26038
The Genome Aggregation Database (gnomAD), exomes 0.28900
Trans-Omics for Precision Medicine (TOPMed) 0.24615
1000 Genomes Project 0.24940
The Genome Aggregation Database (gnomAD) 0.25830
Exome Aggregation Consortium (ExAC) 0.29500
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.25957
Links
Genetic Testing Registry (GTR): GTR000562560
Genetic Testing Registry (GTR): GTR000593372
UniProtKB: P42898#VAR_014882
OMIM: 607093.0004
dbSNP: rs1801131
PharmGKB Clinical Annotation: 1183705832
ClinGen: CA116320
Genetic Testing Registry (GTR): GTR000500035
Genetic Testing Registry (GTR): GTR000500809
Genetic Testing Registry (GTR): GTR000552460
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Benign 1 criteria provided, single submitter May 28, 2019 RCV000350590.4
Uncertain significance 1 criteria provided, single submitter Jun 23, 2021 RCV002227013.2
Conflicting interpretations of pathogenicity; other 4 criteria provided, conflicting interpretations Oct 21, 2021 RCV000153515.18
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Jul 1, 2021 RCV001197542.6
Benign 1 no assertion criteria provided Jul 1, 2008 RCV000003698.5
Schizophrenia, susceptibility to
risk factor 1 no assertion criteria provided Jul 1, 2008 RCV000003699.5
Uncertain significance 1 no assertion criteria provided - RCV000144922.2
Benign 5 no assertion criteria provided - RCV000430863.12
Benign 1 no assertion criteria provided Sep 16, 2020 RCV001273149.2
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
MTHFR - - GRCh38
GRCh37
501 561

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter More information
other
(Jan 13, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Affected status: unknown
Allele origin: germline
Eurofins NTD LLC (GA)
Accession: SCV000203039.7
First in ClinVar: Feb 02, 2015
Last updated: Dec 06, 2016
Other databases
http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MTHFR
Number of individuals with the variant: 169
Zygosity: 32 Homozygote, 134 Single Heterozygote
Sex: mixed
Benign
(May 28, 2019)
criteria provided, single submitter
Method: clinical testing
Neural tube defects, folate-sensitive
Affected status: unknown
Allele origin: unknown
Mendelics
Accession: SCV001135170.1
First in ClinVar: Jan 09, 2020
Last updated: Jan 09, 2020
Benign
(Jul 01, 2021)
criteria provided, single submitter
Method: clinical testing
Homocystinuria due to methylene tetrahydrofolate reductase deficiency
Affected status: no
Allele origin: germline
Genome-Nilou Lab
Accession: SCV001748535.1
First in ClinVar: Jul 10, 2021
Last updated: Jul 10, 2021
Sex: mixed
Benign
(Feb 25, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Affected status: yes
Allele origin: germline
GeneDx
Accession: SCV000519507.4
First in ClinVar: Mar 08, 2017
Last updated: Mar 08, 2017
Comment:
E429A, commonly reported as c.1298A>C, is a benign variant. It results in reduced MTHFR activity but it is not associated with increased plasma folate concentration … (more)
Benign
(Oct 21, 2021)
criteria provided, single submitter
Method: clinical testing
not provided
Affected status: unknown
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604289.5
First in ClinVar: Mar 08, 2017
Last updated: Jan 08, 2022
Uncertain significance
(Oct 01, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Affected status: yes
Allele origin: germline
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001147148.11
First in ClinVar: Feb 03, 2020
Last updated: Jul 09, 2022
Number of individuals with the variant: 1
Likely pathogenic
(Jan 28, 2019)
criteria provided, single submitter
Method: clinical testing
Homocystinuria due to methylene tetrahydrofolate reductase deficiency
Affected status: yes
Allele origin: unknown
Centre for Mendelian Genomics,University Medical Centre Ljubljana
Accession: SCV001368321.2
First in ClinVar: Jul 06, 2020
Last updated: Jul 06, 2020
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: No criteria apply. This variant was detected in … (more)
Benign
(Nov 26, 2020)
criteria provided, single submitter
Method: clinical testing
Homocystinuria due to methylene tetrahydrofolate reductase deficiency
Affected status: unknown
Allele origin: germline
Invitae
Accession: SCV001733272.1
First in ClinVar: Jun 15, 2021
Last updated: Jun 15, 2021
Uncertain significance
(Jun 23, 2021)
criteria provided, single submitter
Method: clinical testing
Stroke
Affected status: yes
Allele origin: germline
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002506414.1
First in ClinVar: May 07, 2022
Last updated: May 07, 2022
Publications:
PubMed (2)
PubMed: 954539528514598
Comment:
ACMG categories: PS3,PS4,PM1,BA1
Number of individuals with the variant: 1
Clinical Features:
Stroke (present)
Zygosity: 1 Compound Heterozygote
Age: 10-19 years
Sex: male
Tissue: blood
Benign
(Jul 01, 2008)
no assertion criteria provided
Method: literature only
MTHFR THERMOLABILE POLYMORPHISM
Affected status: not provided
Allele origin: germline
OMIM
Accession: SCV000023861.3
First in ClinVar: Apr 04, 2013
Last updated: Dec 31, 2017
Publications:
PubMed (13)
van der Put, N. M. J., Blom, H. J.  (more...)
van der Put, N. M. J., Blom, H. J. Reply to Donnelly. (Letter) Am. J. Hum. Genet. 66: 744-745, 2000.
Comment on evidence:
Van der Put et al. (1998) identified another polymorphism of the MTHFR gene: a 1298A-C mutation resulting in a glu429-to-ala (E429A) substitution. The mutation destroyed … (more)
risk factor
(Jul 01, 2008)
no assertion criteria provided
Method: literature only
SCHIZOPHRENIA, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin: germline
OMIM
Accession: SCV000023862.3
First in ClinVar: Apr 04, 2013
Last updated: Dec 31, 2017
Publications:
PubMed (13)
van der Put, N. M. J., Blom, H. J.  (more...)
van der Put, N. M. J., Blom, H. J. Reply to Donnelly. (Letter) Am. J. Hum. Genet. 66: 744-745, 2000.
Comment on evidence:
Van der Put et al. (1998) identified another polymorphism of the MTHFR gene: a 1298A-C mutation resulting in a glu429-to-ala (E429A) substitution. The mutation destroyed … (more)
Benign
(-)
no assertion criteria provided
Method: clinical testing
not specified
Affected status: yes
Allele origin: germline
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741945.3
First in ClinVar: Jul 07, 2021
Last updated: Sep 08, 2021
Benign
(-)
no assertion criteria provided
Method: clinical testing
not specified
Affected status: yes
Allele origin: germline
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928366.1
First in ClinVar: Sep 26, 2021
Last updated: Sep 26, 2021
Uncertain significance
(-)
no assertion criteria provided
Method: case-control
Gastrointestinal Stromal Tumors
Affected status: yes
Allele origin: germline
Department of Pharmacy and Biotechnology,University of Bologna
Accession: SCV000187679.1
First in ClinVar: Nov 13, 2014
Last updated: Nov 13, 2014
Publications:
PubMed (1)
PubMed: 25227144
Number of individuals with the variant: 36
Zygosity: 8 Homozygote, 28 Single Heterozygote
Benign
(Sep 16, 2020)
no assertion criteria provided
Method: clinical testing
Homocystinuria due to MTHFR deficiency
Affected status: unknown
Allele origin: germline
Natera, Inc.
Accession: SCV001455754.1
First in ClinVar: Jan 02, 2021
Last updated: Jan 02, 2021
Benign
(-)
no assertion criteria provided
Method: clinical testing
not specified
Affected status: yes
Allele origin: germline
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919429.1
First in ClinVar: Sep 26, 2021
Last updated: Sep 26, 2021
Benign
(-)
no assertion criteria provided
Method: clinical testing
not specified
Affected status: yes
Allele origin: germline
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956936.1
First in ClinVar: Oct 02, 2021
Last updated: Oct 02, 2021
Benign
(-)
no assertion criteria provided
Method: clinical testing
not specified
Affected status: yes
Allele origin: germline
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037998.1
First in ClinVar: Dec 25, 2021
Last updated: Dec 25, 2021

Functional evidence

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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 this variant

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Title Author Journal Year Link
The communal relation of MTHFR, MTR, ACE gene polymorphisms and hyperhomocysteinemia as conceivable risk of coronary artery disease. Masud R Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 2017 PMID: 28514598
Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome. Angelini S European journal of human genetics : EJHG 2015 PMID: 25227144
Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Allen NC Nature genetics 2008 PMID: 18583979
Congenital heart defects and genetic variants in the methylenetetrahydroflate reductase gene. Hobbs CA Journal of medical genetics 2006 PMID: 15951337
Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian population. Kumar J Journal of human genetics 2005 PMID: 16244782
'Racial' differences in genetic effects for complex diseases. Ioannidis JP Nature genetics 2004 PMID: 15543147
Methylenetetrahydrofolate reductase enzyme polymorphisms as maternal risk for Down syndrome among Turkish women. Boduroğlu K American journal of medical genetics. Part A 2004 PMID: 15103709
Genotype and haplotype distributions of MTHFR677C>T and 1298A>C single nucleotide polymorphisms: a meta-analysis. Ogino S Journal of human genetics 2003 PMID: 12560871
Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos. Zetterberg H European journal of human genetics : EJHG 2002 PMID: 11938441
Genetic diversity and disease: opportunities and challenge. Scott JM Proceedings of the National Academy of Sciences of the United States of America 2001 PMID: 11752418
Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Yamada K Proceedings of the National Academy of Sciences of the United States of America 2001 PMID: 11742092
Examinations of methylenetetrahydrofolate reductase C677T and A1298C mutations--and in utero viability. Volcik KA American journal of human genetics 2001 PMID: 11590551
Neonatal and fetal methylenetetrahydrofolate reductase genetic polymorphisms: an examination of C677T and A1298C mutations. Isotalo PA American journal of human genetics 2000 PMID: 10958762
The 1298(A-->C) mutation of methylenetetrahydrofolate reductase should be designated to the 1289 position of the gene. Donnelly JG American journal of human genetics 2000 PMID: 10677336
A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? van der Put NM American journal of human genetics 1998 PMID: 9545395
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MTHFR - - - -
van der Put, N. M. J., Blom, H. J. Reply to Donnelly. (Letter) Am. J. Hum. Genet. 66: 744-745, 2000. - - - -

Text-mined citations for rs1801131...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 03, 2022