NM_005957.5(MTHFR):c.1286A>C (p.Glu429Ala)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Benign/Likely benign; other
Benign (10); Likely benign (1)
Benign (10); Likely benign (1)
12 out of 24 submissions contributed to this classification
Help
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.
24
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005957.5(MTHFR):c.1286A>C (p.Glu429Ala)
Variation ID: 3521 Accession: VCV000003521.146
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p36.22 1: 11794419 (GRCh38) [ NCBI UCSC ] 1: 11854476 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Nov 13, 2014 Jun 27, 2026 Feb 4, 2026 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005957.5:c.1286A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005948.3:p.Glu429Ala missense NM_001330358.2:c.1409A>C NP_001317287.1:p.Glu470Ala missense NC_000001.11:g.11794419T>G NC_000001.10:g.11854476T>G NG_013351.1:g.16685A>C LRG_726:g.16685A>C LRG_726t1:c.1286A>C LRG_726p1:p.Glu429Ala P42898:p.Glu429Ala - Protein change
- E470A
- Other names
-
MTHFR, 1298A-C, GLU429ALA (rs1801131)
E429A
- Canonical SPDI
- NC_000001.11:11794418:T:G
-
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.
-
0.24940 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.24360
Trans-Omics for Precision Medicine (TOPMed) 0.24615
1000 Genomes Project 0.24940
The Genome Aggregation Database (gnomAD) 0.25830
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.25957
The Genome Aggregation Database (gnomAD) 0.26352
The Genome Aggregation Database (gnomAD), exomes 0.28900
Exome Aggregation Consortium (ExAC) 0.29500
The Genome Aggregation Database (gnomAD), exomes 0.30750
- Links
-
ClinPGx Clinical Annotation: 1183705832 ClinGen: CA116320 Genetic Testing Registry (GTR): GTR000500035 Genetic Testing Registry (GTR): GTR000500809 Genetic Testing Registry (GTR): GTR000569929 Genetic Testing Registry (GTR): GTR000593372 Genetic Testing Registry (GTR): GTR000613302 Genetic Testing Registry (GTR): GTR000619762 UniProtKB: P42898#VAR_014882 OMIM: 607093.0004 dbSNP: rs1801131 VarSome
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| MTHFR | Gene associated with autosomal recessive phenotype | Not yet evaluated |
GRCh38 GRCh37 |
986 | 1054 | |
Conditions - Germline
| Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Benign (1) |
no assertion criteria provided
|
Jul 1, 2008 | RCV000003698.12 | |
| risk factor (1) |
no assertion criteria provided
|
Jul 1, 2008 | RCV000003699.12 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Oct 30, 2023 | RCV000144922.10 | |
| Benign; other (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 17, 2025 | RCV000153515.58 | |
| Benign (1) |
criteria provided, single submitter
|
May 28, 2019 | RCV000350590.11 | |
| Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
|
Feb 16, 2025 | RCV000430863.21 | |
| Benign (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 4, 2026 | RCV001197542.26 | |
|
MTHFR-related disorder
|
Benign (1) |
no assertion criteria provided
|
Dec 1, 2023 | RCV003974792.2 |
| Benign (1) |
criteria provided, single submitter
|
Apr 17, 2023 | RCV005394111.1 | |
| Likely risk allele (1) |
no assertion criteria provided
|
Jun 8, 2026 | RCV006707577.1 |
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. |
Expand all rows
Collapse all rows
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. |
|
|---|---|---|---|---|---|
|
Benign
(May 28, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neural tube defects, folate-sensitive |
Mendelics
Accession: SCV001135170.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
other
Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
(Jan 13, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000203039.8
First in ClinVar: Feb 02, 2015 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 169
Zygosity: 32 Homozygotes, 134 Single Heterozygotes
Sex: mixed
|
|
|
Benign
(Feb 25, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000519507.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
show
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 in the heterozygous or homozygous state. This variant is present in 31% of alleles in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9545395, 18842806, 21241403, 22882325, 18836720, 21577095, 20135343, 23652803, 18992148, 23162020, 23771968, 19936946, 19837268, 20031554, 19232336, 19356065, 11875032, 22102315, 21897766, 21334398, 21845428, 20935396, 20532637, 21080081, 18583979, 21613384, 19854238, 21107737, 11395038, 9719624, 26238013, 27068821, 27330833, 23659764, 24109560, 23685927, 11274424, 29600437, 24440586, 22051736, 29395581, 20078877, 24175756, 24488901, 24301776, 22576927, 25573130, 29974397, 26135458, 23523621, 16489479) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(Mar 25, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Homocystinuria due to methylene tetrahydrofolate reductase deficiency |
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Accession: SCV004805343.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Jul 01, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Homocystinuria due to methylene tetrahydrofolate reductase deficiency |
Genome-Nilou Lab
Accession: SCV001748535.2
First in ClinVar: Jul 10, 2021 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Sex: mixed
|
|
|
Benign
(Dec 06, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Homocystinuria due to methylene tetrahydrofolate reductase deficiency |
Centre of Medical Genetics, University Hospital Muenster
Accession: SCV002506414.3
First in ClinVar: May 07, 2022 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Stroke disorder (present)
Zygosity: 1 Compound Heterozygote
Age: 10-19 years
Sex: male
Tissue: blood
|
|
|
Benign
(Apr 17, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Schizophrenia
Thrombophilia due to thrombin defect Homocystinuria due to methylene tetrahydrofolate reductase deficiency Neural tube defects, folate-sensitive
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
Department of Pathology and Laboratory Medicine, Sinai Health System
Accession: SCV006054864.1
First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Feb 16, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Laboratory of Genetics, Children's Clinical University Hospital Latvia
Accession: SCV006105658.1
First in ClinVar: Jul 05, 2025 Last updated: Jul 05, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(Jul 17, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604289.10
First in ClinVar: Mar 08, 2017 Last updated: Jan 24, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Feb 04, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Homocystinuria due to methylene tetrahydrofolate reductase deficiency |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001733272.5
First in ClinVar: Jun 15, 2021 Last updated: Mar 07, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Sep 07, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004099611.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
show
Variant summary: MTHFR c.1286A>C (p.Glu429Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.29 in 251462 control chromosomes in the gnomAD database, including 11567 homozygotes strongly suggesting that the variant is benign. This variant, c.1286A>C is also known as 1298A>C. One publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity and homocysteine levels for heterozygotes and homozygotes were not different from those with the wild type genotype, supporting the idea that this polymorphism alone might not significantly affect homocysteine metabolism (example: Weisberg_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11395038). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as Benign/likely benign (n=7), uncertain significance (n=1), risk factor (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(May 01, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001147148.37
First in ClinVar: Feb 03, 2020 Last updated: Jun 20, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 5
|
|
|
Benign
(Sep 16, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Homocystinuria due to MTHFR deficiency |
Natera, Inc.
Accession: SCV001455754.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not specified |
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 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(Jul 01, 2008)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
MTHFR THERMOLABILE POLYMORPHISM |
OMIM
Accession: SCV000023861.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2017 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
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)
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 an MboII recognition site and had an allele frequency of 0.33. Whereas the 677C-T transition (607093.0003) occurs within the predicted catalytic domain of the MTHFR enzyme, the 1298A-C transversion is located in the presumed regulatory domain. The 1298A-C mutation resulted in decreased MTHFR activity, which was more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state was associated with higher plasma homocysteine (Hcy) nor a lower plasma folate concentration--phenomena that are evident with homozygosity for the 677C-T mutation. However, van der Put et al. (1998) found that combined heterozygosity at the 2 polymorphic sites was associated with reduced MTHFR-specific activity, higher Hcy, and decreased plasma folate levels. Thus, combined heterozygosity for both MTHFR mutations resulted in features similar to those observed in homozygotes for the 677C-T mutation. This combined heterozygosity was observed in 28% of the neural tube defect (NTD) patients compared with 20% among controls, resulting in an odds ratio of 2.04. The data suggested that combined heterozygosity for the 2 common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677C-T mutation. Yamada et al. (2001) studied the biochemical characteristics of the products of both the 677C-T and the 1298A-C polymorphisms by overexpressing the genes and purifying the protein to homogeneity in quantities suitable for the characterization. The E429A protein had biochemical properties indistinguishable from the wildtype enzyme. The A222V MTHFR, however, had an enhanced propensity to dissociate into monomers and to lose its FAD cofactor on dilution. Protein that had both changes revealed no additive effect in these biochemical studies. This prompted Scott (2001) to suggest that the claim of van der Put et al. (1998) that the double variant increases risk needed to be reevaluated. Donnelly (2000) argued that the change described by van der Put et al. (1998) as 1298A-C is in fact 1289A-C. The mutation was expected to change the codon from GAA (glu) to GCA (ala). In a reply to Donnelly (2000), van der Put and Blom (2000) stated that the second SNP was designated 1298A-C for consistency with the first SNP, 677C-T. Although the first SNP was said to occur at nucleotide 677, the actual location may be nucleotide 665 of the coding region. Isotalo et al. (2000) analyzed 119 neonatal cord blood samples and 161 fetal tissue samples for MTHFR 677C-T and 1298A-C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis demonstrated that all possible MTHFR genotype combinations were represented in the fetal group; 677T and 1298C alleles could occur in either cis or trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contained 3 and 4 mutant alleles, respectively, were not observed in the neonatal group (p = 0.0402). This suggested decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This was the first report to describe the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrated their potential role in compromised fetal viability. Volcik et al. (2001) presented data supporting the conclusion of Isotalo et al. (2000) concerning decreased viability among fetuses with the 677TT/1298CC genotype, which they did not observe in the United States and Canadian populations studied. Because they observed, in 3 different populations, the 677CT/1298CC genotype in frequencies nearing those expected, Volcik et al. (2001) concluded that this genotype does not result in a significant selective disadvantage. Zetterberg et al. (2002) examined the distribution of the 677C-T and 1298A-C polymorphisms in 80 fetal tissue samples from spontaneous abortions occurring between the sixth and twentieth week of pregnancy, compared to 125 healthy blood donors (both cases and controls were from Crete, Greece). Only 1 of the 80 spontaneously aborted embryos had the wildtype combined genotype 677CC/1298AA as compared to 19 of 125 controls (p = 0.001). Combined genotypes which contain 3 or 4 mutant alleles were not detected in any of the groups, suggesting complete linkage disequilibrium between the 2 polymorphisms. A significant odds ratio of 14.2 (95% CI, 1.78-113) for spontaneous abortion was obtained when comparing the prevalence of at least 1 MTHFR mutation in abortions and controls (p = 0.001). Zetterberg et al. (2002) concluded from the data that the effect of 1 or more MTHFR mutated alleles may be detrimental during embryogenesis when the folate requirement is high. Both the 677C-T and 1298A-C SNPs in the MTHFR gene decrease the activity of the enzyme, leading to hyperhomocysteinemia (603174), particularly in folate-deficient states. Ogino and Wilson (2003) calculated the haplotype frequencies of the polymorphisms at nucleotides 677 and 1298 in pooled general populations derived from data published in 16 articles. They found that most 677T and 1298C alleles were associated with 1298A and 677C alleles, respectively. There may be an increased frequency of the very rare cis 677T/1298C haplotype in some parts of the United Kingdom and Canada, possibly due to a founder effect. Among Turkish women, Boduroglu et al. (2004) could find no support for a relationship between the 677C-T and 1298A-C SNPs in the MTHFR gene and risk of having a child with Down syndrome (190685). Among 200 Indian individuals, Kumar et al. (2005) found that plasma homocysteine levels were significantly increased in those adhering to a vegetarian diet and in those with a 1298C allele. However, the increase in homocysteine levels in vegetarians was irrespective of MTHFR genotype. Among a larger group of over 400 Indian individuals, Kumar et al. (2005) found that the frequency of the 1298CC genotype was 19.46%, which was much higher than that reported for Caucasian (9.4%), Chinese (3.3%), or Japanese (1.6%) populations. The authors concluded that the 1298A-C polymorphism is relevant for increased plasma homocysteine levels in the Indian population. Hobbs et al. (2006) observed an apparent protective effect of the MTHFR 1298C allele against congenital heart defect. Allen et al. (2008) performed a metaanalysis comparing 1,211 cases of schizophrenia with 1,729 controls and found that the MTHFR 1298C allele (1801133) was associated with susceptibility to schizophrenia (odds ratio, 1.19; 95% CI, 1.07- 1.34; p = 0.002). According to the Venice guidelines for the assessment of cumulative evidence in genetic association studies (Ioannidis et al., 2008), the MTHFR association showed a 'strong' degree of epidemiologic credibility. (less)
|
|
|
risk factor
(Jul 01, 2008)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
SCHIZOPHRENIA, SUSCEPTIBILITY TO |
OMIM
Accession: SCV000023862.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2017 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
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)
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 an MboII recognition site and had an allele frequency of 0.33. Whereas the 677C-T transition (607093.0003) occurs within the predicted catalytic domain of the MTHFR enzyme, the 1298A-C transversion is located in the presumed regulatory domain. The 1298A-C mutation resulted in decreased MTHFR activity, which was more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state was associated with higher plasma homocysteine (Hcy) nor a lower plasma folate concentration--phenomena that are evident with homozygosity for the 677C-T mutation. However, van der Put et al. (1998) found that combined heterozygosity at the 2 polymorphic sites was associated with reduced MTHFR-specific activity, higher Hcy, and decreased plasma folate levels. Thus, combined heterozygosity for both MTHFR mutations resulted in features similar to those observed in homozygotes for the 677C-T mutation. This combined heterozygosity was observed in 28% of the neural tube defect (NTD) patients compared with 20% among controls, resulting in an odds ratio of 2.04. The data suggested that combined heterozygosity for the 2 common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677C-T mutation. Yamada et al. (2001) studied the biochemical characteristics of the products of both the 677C-T and the 1298A-C polymorphisms by overexpressing the genes and purifying the protein to homogeneity in quantities suitable for the characterization. The E429A protein had biochemical properties indistinguishable from the wildtype enzyme. The A222V MTHFR, however, had an enhanced propensity to dissociate into monomers and to lose its FAD cofactor on dilution. Protein that had both changes revealed no additive effect in these biochemical studies. This prompted Scott (2001) to suggest that the claim of van der Put et al. (1998) that the double variant increases risk needed to be reevaluated. Donnelly (2000) argued that the change described by van der Put et al. (1998) as 1298A-C is in fact 1289A-C. The mutation was expected to change the codon from GAA (glu) to GCA (ala). In a reply to Donnelly (2000), van der Put and Blom (2000) stated that the second SNP was designated 1298A-C for consistency with the first SNP, 677C-T. Although the first SNP was said to occur at nucleotide 677, the actual location may be nucleotide 665 of the coding region. Isotalo et al. (2000) analyzed 119 neonatal cord blood samples and 161 fetal tissue samples for MTHFR 677C-T and 1298A-C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis demonstrated that all possible MTHFR genotype combinations were represented in the fetal group; 677T and 1298C alleles could occur in either cis or trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contained 3 and 4 mutant alleles, respectively, were not observed in the neonatal group (p = 0.0402). This suggested decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This was the first report to describe the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrated their potential role in compromised fetal viability. Volcik et al. (2001) presented data supporting the conclusion of Isotalo et al. (2000) concerning decreased viability among fetuses with the 677TT/1298CC genotype, which they did not observe in the United States and Canadian populations studied. Because they observed, in 3 different populations, the 677CT/1298CC genotype in frequencies nearing those expected, Volcik et al. (2001) concluded that this genotype does not result in a significant selective disadvantage. Zetterberg et al. (2002) examined the distribution of the 677C-T and 1298A-C polymorphisms in 80 fetal tissue samples from spontaneous abortions occurring between the sixth and twentieth week of pregnancy, compared to 125 healthy blood donors (both cases and controls were from Crete, Greece). Only 1 of the 80 spontaneously aborted embryos had the wildtype combined genotype 677CC/1298AA as compared to 19 of 125 controls (p = 0.001). Combined genotypes which contain 3 or 4 mutant alleles were not detected in any of the groups, suggesting complete linkage disequilibrium between the 2 polymorphisms. A significant odds ratio of 14.2 (95% CI, 1.78-113) for spontaneous abortion was obtained when comparing the prevalence of at least 1 MTHFR mutation in abortions and controls (p = 0.001). Zetterberg et al. (2002) concluded from the data that the effect of 1 or more MTHFR mutated alleles may be detrimental during embryogenesis when the folate requirement is high. Both the 677C-T and 1298A-C SNPs in the MTHFR gene decrease the activity of the enzyme, leading to hyperhomocysteinemia (603174), particularly in folate-deficient states. Ogino and Wilson (2003) calculated the haplotype frequencies of the polymorphisms at nucleotides 677 and 1298 in pooled general populations derived from data published in 16 articles. They found that most 677T and 1298C alleles were associated with 1298A and 677C alleles, respectively. There may be an increased frequency of the very rare cis 677T/1298C haplotype in some parts of the United Kingdom and Canada, possibly due to a founder effect. Among Turkish women, Boduroglu et al. (2004) could find no support for a relationship between the 677C-T and 1298A-C SNPs in the MTHFR gene and risk of having a child with Down syndrome (190685). Among 200 Indian individuals, Kumar et al. (2005) found that plasma homocysteine levels were significantly increased in those adhering to a vegetarian diet and in those with a 1298C allele. However, the increase in homocysteine levels in vegetarians was irrespective of MTHFR genotype. Among a larger group of over 400 Indian individuals, Kumar et al. (2005) found that the frequency of the 1298CC genotype was 19.46%, which was much higher than that reported for Caucasian (9.4%), Chinese (3.3%), or Japanese (1.6%) populations. The authors concluded that the 1298A-C polymorphism is relevant for increased plasma homocysteine levels in the Indian population. Hobbs et al. (2006) observed an apparent protective effect of the MTHFR 1298C allele against congenital heart defect. Allen et al. (2008) performed a metaanalysis comparing 1,211 cases of schizophrenia with 1,729 controls and found that the MTHFR 1298C allele (1801133) was associated with susceptibility to schizophrenia (odds ratio, 1.19; 95% CI, 1.07- 1.34; p = 0.002). According to the Venice guidelines for the assessment of cumulative evidence in genetic association studies (Ioannidis et al., 2008), the MTHFR association showed a 'strong' degree of epidemiologic credibility. (less)
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Benign
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
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not specified |
Clinical Genetics, Academic Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001919429.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Benign
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not specified |
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV001928366.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Benign
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
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not specified |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV002037998.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Benign
(Dec 01, 2023)
N
Not contributing to aggregate classification
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no assertion criteria provided
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MTHFR-related condition
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PreventionGenetics, part of Exact Sciences
Accession: SCV004794374.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
show
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
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Benign
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
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not specified |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Study: VKGL Data-share Consensus
Accession: SCV001956936.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Likely risk allele
(Jun 08, 2026)
N
Not contributing to aggregate classification
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no assertion criteria provided
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Stroke disorder
(Sporadic)
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Department of Clinical Medical Laboratory, The Second Hospital of Lanzhou University
Accession: SCV007601568.1
First in ClinVar: Jun 27, 2026 Last updated: Jun 27, 2026 |
Comment:
show
Case-control association study of MTHFR A1298C (c.1286A>C, rs1801131) and ischemic stroke in a Chinese Han population. Study included 121 ischemic stroke patients and 121 healthy controls. The C allele frequency was significantly higher in cases (21.07%) than controls (13.64%). OR=1.64, 95% CI=1.02-2.66, P=0.042. Genotypes in cases: AA=81, AC=29, CC=11; in controls: AA=87, AC=29, CC=2. (less)
Observation:
2
Observation 1
Collection method: case-control
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 40
Test name: PCR-RFLP
Zygosity: 11 Homozygotes, 29 Single Heterozygotes
Sex: mixed
Ethnicity/Population group: Han Chinese
Geographic origin: China
Platform type: PCR
Observation 2
Collection method: case-control
Allele origin: germline
Affected status: no
Number of individuals with the variant: 31
Zygosity: 2 Homozygotes, 29 Single Heterozygotes
Sex: mixed
Ethnicity/Population group: Han Chinese
Geographic origin: China
Platform Type: PCR
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Likely pathogenic
(Jan 28, 2019)
N
Not contributing to aggregate classification
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Flagged submission
flagged submission
Reason: Outlier claim with insufficient supporting evidence
Notes: Likely pathogenic classification is not possible if no criteria are applicable.
(less)
Notes: Likely pathogenic
(...more)
Source: ClinGen
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Homocystinuria due to methylene tetrahydrofolate reductase deficiency |
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368321.2
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
show
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 homozygous state. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
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Uncertain significance
(-)
N
Not contributing to aggregate classification
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Flagged submission
flagged submission
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Gastrointestinal Stromal Tumors
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Department of Pharmacy and Biotechnology, University of Bologna
Accession: SCV000187679.1
First in ClinVar: Nov 13, 2014 Last updated: Nov 13, 2014 |
Observation 1
Collection method: case-control
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 36
Zygosity: 8 Homozygotes, 28 Single Heterozygotes
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Citation text
van der Put, N. M. J., Blom, H. J. Reply to Donnelly. (Letter) Am. J. Hum. Genet. 66: 744-745, 2000.
Citation text
van der Put, N. M. J., Blom, H. J. Reply to Donnelly. (Letter) Am. J. Hum. Genet. 66: 744-745, 2000.
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 in the heterozygous or homozygous state. This variant is present in 31% of alleles in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9545395, 18842806, 21241403, 22882325, 18836720, 21577095, 20135343, 23652803, 18992148, 23162020, 23771968, 19936946, 19837268, 20031554, 19232336, 19356065, 11875032, 22102315, 21897766, 21334398, 21845428, 20935396, 20532637, 21080081, 18583979, 21613384, 19854238, 21107737, 11395038, 9719624, 26238013, 27068821, 27330833, 23659764, 24109560, 23685927, 11274424, 29600437, 24440586, 22051736, 29395581, 20078877, 24175756, 24488901, 24301776, 22576927, 25573130, 29974397, 26135458, 23523621, 16489479)
Comment:
ACMG categories: BA1, BP4
Comment:
Variant summary: MTHFR c.1286A>C (p.Glu429Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.29 in 251462 control chromosomes in the gnomAD database, including 11567 homozygotes strongly suggesting that the variant is benign. This variant, c.1286A>C is also known as 1298A>C. One publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity and homocysteine levels for heterozygotes and homozygotes were not different from those with the wild type genotype, supporting the idea that this polymorphism alone might not significantly affect homocysteine metabolism (example: Weisberg_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11395038). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as Benign/likely benign (n=7), uncertain significance (n=1), risk factor (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
MTHFR: BS1, BS2
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Comment:
Case-control association study of MTHFR A1298C (c.1286A>C, rs1801131) and ischemic stroke in a Chinese Han population. Study included 121 ischemic stroke patients and 121 healthy controls. The C allele frequency was significantly higher in cases (21.07%) than controls (13.64%). OR=1.64, 95% CI=1.02-2.66, P=0.042. Genotypes in cases: AA=81, AC=29, CC=11; in controls: AA=87, AC=29, CC=2.
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 homozygous state.
Citations for germline classification of this variant
Help| 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 |
| The 1298A-->C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. | Weisberg IS | Atherosclerosis | 2001 | PMID: 11395038 |
| 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 | - | - | - | - |
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Text-mined citations for rs1801131 ...
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Record last updated Jul 15, 2026
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.