The MTHFR NM_005957.5:c.1286A>C (NP_005948.3:p.(Glu429Ala)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Two variant-specific studies found reduced MTHFR activity, including 68% of wild type and ANOVA P < .0001, but a purified-enzyme study was discordant. Purified recombinant Glu429Ala MTHFR had wild-type biochemical properties, but other variant-specific assays reported reduced activity. Based on available guidelines, this variant is considered to be Benign.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MTHFR encodes an enzyme that helps process folate and supports the conversion of homocysteine into methionine, an essential building block for the body. Changes in this gene can cause methylenetetrahydrofolate reductase deficiency and may influence susceptibility to vascular disease and neural tube defects. MTHFR has been studied in colon cancer, acute leukemia, and other cancers, but there is insufficient evidence to classify it as an oncogene or tumor suppressor.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting: two variant-specific studies found reduced MTHFR activity, including 68% of wild type and ANOVA P < .0001, but a purified-enzyme study was discordant.
Met: gnomAD v4.1 grpmax FAF 0.407473 exceeds the 0.05 BA1 threshold in a South Asian group with 91,062 observed alleles.
Met strong: gnomAD v4.1 grpmax FAF 0.407473 is far above the generic BS1 0.01 threshold in a large ancestry sample.
Met at supporting: purified recombinant Glu429Ala MTHFR had wild-type biochemical properties, but other variant-specific assays reported reduced activity.
Met at supporting strength: REVEL 0.197 is at or below the generic BP4 supporting threshold of 0.29 for this missense variant.
Benign: BA1 stand-alone benign is met by the gnomAD filtering allele frequency of 0.407473, exceeding the generic 0.05 threshold.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 489,287 / 1,613,542 alleles. Recorded AF 0.303238. Recorded homozygote count 76973.
This variant is present in gnomAD v2.1 (AF= 0.285829; MAF= 28.58295%, 80824/282770 alleles, homozygotes = 12683) and has highest observed frequency in the South Asian population (AF= 0.411648; MAF= 41.16475%, 12603/30616 alleles, homozygotes = 2645); grpmax FAF= 0.405634.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.197. Refer to the recorded PP3/BP4 rationale for interpretation.
15 Benign · 1 Likely benign · 1 other · 1 Uncertain significance · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MTHFR, a reductase in the folate cycle, is altered in various cancers.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 5 not met · 14 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No segregation or de novo criterion is applied because the available evidence is population-level rather than an individual pedigree or trio analysis.
The functional evidence is bidirectional: variant-specific assays report both reduced activity and wild-type biochemical behavior.
Both PS3 and BS3 are retained only at supporting strength because the studies are not documented as validated clinical diagnostic assays and are materially discordant.
Human review is required to adjudicate assay comparability, controls, and the biological significance of the measured activity differences.
PS4 is not met because the exact A1298C genotype OR was 2.50 (95% CI 1.38-4.53), below the generic OR >5.0 threshold; the reported OR 14.2 applied to a combined MTHFR-mutation endpoint rather than this exact variant.
PP4 and BP5 are not assessed because the case lacks the phenotype/family-history and alternate-molecular-basis details required by their definitions.
PP5 and BP6 are not met because ClinVar has no exact-variant expert-panel submission; non-expert, aggregate, and conflicting assertions are excluded by the specified rule.
BA1 and BS1 are met from large-sample gnomAD filtering allele frequencies of approximately 0.41, well above the generic 0.05 and 0.01 thresholds; these values are not small-isolate popmax artifacts.
BS2 is not assessed because aggregate gnomAD homozygote counts do not document healthy adult individuals or establish the required fully penetrant early-onset disorder model.
PM2 is not met because the variant is common in both gnomAD v2.1 and v4.1 and has thousands of homozygous observations.
No criteria match.
PS3 is met at supporting strength. Two variant-specific functional studies report reduced MTHFR activity for A1298C/Glu429Ala: Weisberg et al. measured 68% +/- 5.0% of wild-type control activity in bacterial extracts after site-directed mutagenesis and in vitro expression, and van der Put et al. reported significantly decreased activity (ANOVA P < .0001), more pronounced in homozygotes. These are biologically relevant enzyme-activity assays and directly evaluate the variant, but they were not shown to be validated, reproducible clinical-laboratory assays. The evidence is also internally discordant because Yamada et al.'s purified recombinant human-enzyme study found Glu429Ala biochemical properties indistinguishable from wild type; therefore PS3 is not assigned at strong strength and requires human review.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
BA1 is met under the generic ACMG/AMP threshold. The default all-comers gnomAD v4.1 record is appropriate because no VCEP specifies a non-cancer or exome-only subset; its filtering allele frequency is grpmax FAF 0.407473, far above the BA1 threshold of 0.05. The relevant highest-frequency ancestry is South Asian with 37,423/91,062 observed alleles, exceeding the minimum 2,000 observed alleles required for use of the population frequency. The frequency is also broadly high across large ancestry groups, not confined to a small isolate. ClinVar has 15 benign and 1 likely-benign laboratory submissions versus one likely-pathogenic submission, so the available consensus does not establish the documented pathogenic-association conflict that would require withholding a stand-alone BA1 call.
BA1: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is met at the generic strong level. The gnomAD v4.1 filtering allele frequency is grpmax FAF 0.407473, exceeding the generic BS1 default threshold of 0.01 by a wide margin; gnomAD v2.1 is concordant at grpmax FAF 0.405634. The frequency is supported by a large South Asian sample of 91,062 observed alleles and is high across several large ancestry groups, rather than being an isolate-only popmax artifact. No governing disorder-specific prevalence, penetrance, or allelic-heterogeneity model is supplied that would establish a maximum credible allele frequency above this value, and the variant's high frequency is not limited to one founder ancestry; therefore the generic BS1 default is applicable.
BS1: Allele frequency is greater than expected for the disorder.
BS3 is met at supporting strength. Yamada et al. used a baculovirus expression system to purify recombinant human MTHFR and performed biochemical characterization; the Glu429Ala protein had biochemical properties indistinguishable from wild type, including comparable kinetic properties, inhibitor response, and FAD-cofactor-release behavior. Scott's contemporaneous commentary likewise states that the 1298A>C variant's FAD-release pattern was identical to wild type and that the polymorphism did not affect catalytic function or regulation. This is a biologically relevant and comparatively thorough functional study, but it was not shown to be validated, reproducible, robust clinical-laboratory testing, and other variant-specific studies reported reduced activity. Accordingly BS3 is limited to supporting strength and requires human review because the functional evidence is contradictory.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense substitution, so the applicable generic computational path is REVEL only; the SpliceAI result is not used for missense BP4. REVEL is 0.197, which is at or below the supplied BP4 supporting threshold of <= 0.29, so BP4 is met at supporting strength. BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
Applied the generic ACMG/AMP PS4 rule: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls." The governing numeric note requires RR or OR >5.0 and a confidence interval that does not include 1.0. PMID:11938441 directly studied A1298C in 80 spontaneously aborted embryos versus 125 healthy controls and reported the exact A1298C allele OR as 1.22 (95% CI 0.798-1.86): 1.22 > 5.0? no; the CI includes 1.0. Its A1298C genotype OR was 2.50 (95% CI 1.38-4.53): 2.50 > 5.0? no. The paper's OR 14.2 (95% CI 1.78-113) was for a combined endpoint of one or more MTHFR mutations versus the wild-type combined genotype, not the exact A1298C variant alone, so it cannot establish PS4 for this variant. PMID:11590551 likewise reported A1298C allele frequencies of 0.146 versus 0.189 in Hispanic patients versus controls and 0.306 versus 0.288 in U.S. European-descent patients versus controls, without evidence meeting the PS4 threshold. Therefore, exact-variant case-control enrichment does not meet the generic PS4 threshold.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM2 is not met. The variant is common in both default all-comers gnomAD datasets: v4.1 reports AF 0.303238 from 489,287/1,613,542 alleles with 76,973 homozygotes, and v2.1 reports AF 0.285829 from 80,824/282,770 alleles with 12,683 homozygotes. These frequencies are many orders of magnitude above the generic PM2 supporting threshold of 0.0001, so the variant is neither absent from controls nor present at an extremely low frequency.
PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The variant is a missense substitution, so the applicable generic computational path is REVEL only; SpliceAI is not used for missense PP3/BP4 and BayesDel has no established generic ACMG-strength calibration. REVEL is 0.197, below the supplied PP3 supporting threshold of >= 0.644 (and below the moderate and strong thresholds), so PP3 is not met.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The governing PP5 definition is not satisfied. ClinVar contains no expert-panel submission for the exact variant; the record is conflicting and consists of ordinary laboratory, research, flagged, and literature-only assertions. The available exact-variant classifications therefore do not constitute the required reputable-source pathogenic report under the specified generic rule.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
The governing BP6 definition is not satisfied. ClinVar contains no expert-panel submission for this exact variant; the benign and likely-benign classifications are ordinary laboratory or literature-only assertions, the record is conflicting, and aggregate or non-expert assertions cannot trigger BP6 under the specified rule.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is MTHFR p.Glu429Ala (c.1286A>C). The available evidence documents this exact change in population and biochemical literature, but does not establish a previously pathogenic variant with the same amino-acid change. The available comparator collection contains no confirmed pathogenic same-amino-acid record, and the exact variant has substantial population frequency (gnomAD v4.1 AF 0.303238) and conflicting ClinVar submissions. A complete pathogenic same-amino-acid search and adjudication of any comparator records are not available in the supplied evidence.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PS2 cannot be assessed because the available evidence does not document a disease-affected proband with this variant, confirmed maternity and paternity, and absence of family history. PMID:11590551 reports A1298C frequencies in patient and parent populations, but does not provide an individual trio-based de novo observation or parental-origin confirmation.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No VCEP-specific domain table applies to MTHFR, and the supplied evidence does not provide a validated MTHFR critical functional domain, mutational hotspot, or evidence that the p.Glu429Ala position lies in such a region without benign variation. The exact variant is common in gnomAD v4.1 (AF 0.303238), which further prevents treating an undocumented region as a PM1 domain without a defined boundary and benign-variation assessment.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The available familial/genotype report describes MTHFR A1298C frequencies and combined 677/1298 genotypes in affected individuals, parents, and controls, but does not document a pathogenic MTHFR variant in trans with c.1286A>C or parent/offspring testing that establishes phase. Therefore, the recessive PM3 requirement cannot be assessed.
For recessive disorders, detected in trans with a pathogenic variant...This requires testing of parents (or offspring) to determine phase.
The target is the missense variant p.Glu429Ala. The supplied PM5 candidate artifact contains zero same-residue candidates and explicitly does not confirm classic PM5 semantics. The reviewed literature documents the target variant but does not provide a different missense substitution at Glu429 that was determined to be pathogenic. A complete pathogenic same-residue comparator review is therefore unavailable.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PM6 cannot be assessed because the available evidence does not document an assumed de novo variant in a disease-affected proband. PMID:11590551 reports population-level A1298C frequencies in patients and parents, without an individual de novo observation or a parental-genotype result sufficient to support assumed de novo status.
Assumed de novo, but without confirmation of paternity and maternity.
PP1 cannot be assessed because no family pedigree demonstrates the variant in multiple affected family members. PMID:11590551 describes population cohorts of patients and parents and allele frequencies, not co-segregation of this variant with disease across affected relatives or a count of informative meioses.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The variant is missense, but the supplied evidence does not establish both required gene-level conditions: a low rate of benign missense variation across MTHFR and missense variants as a common disease mechanism. The exact p.Glu429Ala variant is highly prevalent in gnomAD v4.1 (AF 0.303238), but one variant frequency cannot establish the required gene-wide missense-rate assessment or disease mechanism.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing PP4 rule requires a patient phenotype or family history highly specific for a disease with a single genetic etiology. The supplied case evidence contains no patient phenotype, family history, or disease-specific clinical presentation from which that requirement can be evaluated.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD reports many homozygotes (12,683 in v2.1 and 76,973 in v4.1), but these aggregate population counts do not document individual healthy adults, age, phenotype, or the absence of disease. The case supplies no defined disorder model establishing that full penetrance is expected at an early age, which is required before homozygote observations can be converted into generic BS2 evidence.
BS2: Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
BS4 cannot be assessed because no affected family members with discordant variant status are documented. PMID:11590551 provides population-level patient and parent allele frequencies, but does not identify affected relatives who lack the variant or establish a family-level lack of segregation; therefore the phenocopy caveat cannot be evaluated either.
Lack of segregation in affected members of a family.
The variant is missense, but the supplied evidence does not establish that MTHFR disease is caused primarily by truncating variants. Generic loss-of-function eligibility context is not equivalent to evidence that truncating variants are the primary known disease mechanism, and no curated gene-level variant-spectrum summary is supplied for BP1.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The available familial/genotype report describes A1298C genotypes in patients, parents, and controls, but does not document c.1286A>C in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant. No phase-resolved pathogenic counterpart is available, so BP2 cannot be assessed.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The governing BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease. The available evidence does not document a specific case carrying this exact variant together with a demonstrated alternative molecular diagnosis or molecular cause.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_005957.5:c.1286A>C in MTHFR is a missense substitution predicted to produce NP_005948.3:p.(Glu429Ala). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for MTHFR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_005957.5:c.1286A>C in MTHFR is a missense substitution predicted to produce NP_005948.3:p.(Glu429Ala). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for MTHFR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_005957.5:c.1286A>C in MTHFR is a missense substitution predicted to produce NP_005948.3:p.(Glu429Ala). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for MTHFR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005957.5:c.1286A>C in MTHFR is a missense substitution predicted to produce NP_005948.3:p.(Glu429Ala). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for MTHFR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in MTHFR, mapped onto the exon structure of NM_005957.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| South Asian37423 / 91,062 | 0.417853 hom |
| Middle Eastern2256 / 6,060 | 0.37456 hom |
| European (Finnish)20214 / 63,958 | 0.323172 hom |
| European (non-Finnish)369462 / 1,179,674 | 0.3158190 hom |
| Remaining individuals18966 / 62,492 | 0.32898 hom |
| Ashkenazi Jewish8655 / 29,604 | 0.291303 hom |
| Amish200 / 912 | 0.2222 hom |
| East Asian9266 / 44,842 | 0.21988 hom |
| Admixed American10644 / 60,014 | 0.181041 hom |
| African/African American12201 / 74,924 | 0.161050 hom |
| South Asian12603 / 30,616 | 0.412645 hom |
| European (Finnish)7989 / 25,120 | 0.321257 hom |
| European (non-Finnish)40973 / 129,134 | 0.326625 hom |
| Remaining individuals2136 / 7,220 | 0.3348 hom |
| Ashkenazi Jewish3044 / 10,370 | 0.29457 hom |
| East Asian4391 / 19,944 | 0.22509 hom |
| African/African American4014 / 24,928 | 0.16332 hom |
| Admixed American5674 / 35,438 | 0.16510 hom |
This variant is present in gnomAD v4.1 (AF= 0.303238; MAF= 30.32378%, 489287/1613542 alleles, homozygotes = 76973) and has highest observed frequency in the South Asian population (AF= 0.410962; MAF= 41.09618%, 37423/91062 alleles, homozygotes = 7853); grpmax FAF= 0.407473.
This variant is present in gnomAD v2.1 (AF= 0.285829; MAF= 28.58295%, 80824/282770 alleles, homozygotes = 12683) and has highest observed frequency in the South Asian population (AF= 0.411648; MAF= 41.16475%, 12603/30616 alleles, homozygotes = 2645); grpmax FAF= 0.405634.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, so the applicable generic computational path is REVEL only; the SpliceAI result is not used for missense BP4. REVEL is 0.197, which is at or below the supplied BP4 supporting threshold of <= 0.29, so BP4 is met at supporting strength. BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense substitution, so the applicable generic computational path is REVEL only; SpliceAI is not used for missense PP3/BP4 and BayesDel has no established generic ACMG-strength calibration. REVEL is 0.197, below the supplied PP3 supporting threshold of >= 0.644 (and below the moderate and strong thresholds), so PP3 is not met.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005957.5:c.1286A>C in MTHFR is a missense substitution predicted to produce NP_005948.3:p.(Glu429Ala). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for MTHFR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.197. BayesDel score = -0.22843.
10 paper records listed. 4 cited in the classification.
The activity of the wild-type cDNA was designated as 100%; mutant enzymes containing the 1298 and 677 mutations separately had 68% (+/-5.0) and 45% (+/-10.8), respectively, of control activity
Location Abstract
Context Site-directed mutagenesis of human MTHFR cDNA, in vitro expression, bacterial extracts, enzyme-activity and thermolability assessment; exact protein change is Glu429Ala.
The Glu429Ala protein has biochemical properties that are indistinguishable from the wild-type enzyme.
Location Abstract
Context Baculovirus expression, purification to homogeneity, and biochemical characterization of recombinant human wild-type, Ala222Val, Glu429Ala, and double-mutant MTHFR proteins.
One of the variants (677 C 3 T) brings about an amino acid change from Ala-222 to Val, and the other (1298 A 3 C) changes Glu-429 to Ala.
Location Commentary, discussion of the biochemical study by Yamada et al.; pages 14754–14756
Context Commentary summarizing recombinant-DNA expression and biochemical characterization of purified wild-type, 677 C>T, 1298 A>C, and double-mutant MTHFR enzymes.
This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P < .0001), which is more pronounced in the homozygous than heterozygous state.
Location Abstract
Context Human genotype/phenotype study assessing MTHFR specific activity, plasma homocysteine, and plasma folate across 1298A>C and combined 677C>T/1298A>C genotypes.
We have tested for the MTHFR C677T and A1298C mutations in a Hispanic population of Mexican descent, to determine risk for spina bifida (SB) (Volcik et al. 2000).
Volcik et al. letter, page 1151; Tables 1–3
There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA).
Abstract; Tables 1-3
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.303238; MAF= 30.32378%, 489287/1613542 alleles, homozygotes = 76973) and has highest observed frequency in the South Asian population (AF= 0.410962; MAF= 41.09618%, 37423/91062 alleles, homozygotes = 7853); grpmax FAF= 0.407473.
This variant is present in gnomAD v2.1 (AF= 0.285829; MAF= 28.58295%, 80824/282770 alleles, homozygotes = 12683) and has highest observed frequency in the South Asian population (AF= 0.411648; MAF= 41.16475%, 12603/30616 alleles, homozygotes = 2645); grpmax FAF= 0.405634.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Benign (15 clinical laboratories) and as Likely benign (1 clinical laboratory) and as other (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 3521)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.197. BayesDel score = -0.22843.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MTHFR, a reductase in the folate cycle, is altered in various cancers.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.