Variant classification summary

NM_005957.5:c.1286A>C

MTHFR · NP_005948.3:p.(Glu429Ala) · NM_005957.5

GRCh37: chr1:11854476 T>G · GRCh38: chr1:11794419 T>G

Gene: MTHFR Transcript: NM_005957.5

Final call

Benign

PS3 supporting BA1 stand-alone benign BS1 strong BS3 supporting BP4 supporting

Variant details

Gene

MTHFR

Transcript

NM_005957.5

Protein

NP_005948.3:p.(Glu429Ala)

gnomAD AF

0.30323784568359546 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Supporting pathogenic evidence: PS3 reports reduced MTHFR activity but does not satisfy a pathogenic combination rule.

2

Benign: BA1 is met because gnomAD v4.1 filtering allele frequency is 0.407473, above the 0.05 threshold.

3

Benign: BS1 is met at strong strength because gnomAD v4.1 filtering allele frequency is 0.407473, above the 0.01 threshold.

4

Benign: BS3 reports wild-type biochemical properties for purified Glu429Ala MTHFR at supporting strength.

5

Benign: BP4 is met at supporting strength because REVEL is 0.197, below the 0.29 threshold.

Final determination: Under generic ACMG/AMP 2015 fallback rules, BA1 alone is sufficient for a Benign classification; the applied benign evidence therefore outweighs no qualifying pathogenic combination.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no confirmed previously pathogenic same-amino-acid change is documented, while p.Glu429Ala has gnomAD v4.1 allele frequency 0.303238.	clinvar gnomad_v4 PMID:11752418 PMID:11590551
PS2	Not assessed	Not assessed: patient-parent population frequencies are reported, but no individual proband, confirmed maternity and paternity, or no-family-history de novo observation is documented.	PMID:11590551
PS3	Met	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.	PMID:11395038 PMID:9545395 PMID:11742092 PMID:11590551
PS4	Not met	Not met: exact A1298C genotype OR was 2.50 (95% CI 1.38–4.53), below the required OR >5.0 threshold.	PMID:11938441 PMID:11590551
PM1	Not assessed	Not assessed: no validated MTHFR hotspot or critical domain covering residue 429 is supplied, and the variant's gnomAD v4.1 frequency is 0.303238.	gnomad_v4 hotspots cosmic
PM2	Not met	Not met: gnomAD v4.1 AF 0.303238 and 76,973 homozygotes are incompatible with the PM2 <=0.0001 threshold.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no parent/offspring phase testing demonstrates c.1286A>C in trans with a pathogenic MTHFR allele.	PMID:11590551
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: zero confirmed pathogenic alternate missense comparators at Glu429 are supplied for the target p.Glu429Ala change.	pm5_candidates PMID:11752418 PMID:11590551
PM6	Not assessed	Not assessed: population frequencies in patients and parents do not establish an assumed de novo variant in an individual disease-affected proband.	PMID:11590551
PP1	Not assessed	Not assessed: patient-parent cohort frequencies are available, but no pedigree shows co-segregation across multiple affected family members or informative meioses.	PMID:11590551
PP2	Not assessed	Not assessed: the required gene-wide benign-missense rate and common missense disease mechanism are not established; p.Glu429Ala has gnomAD v4.1 AF 0.303238.	gnomad_v4 clinvar
PP3	Not met	Not met: REVEL 0.197 is below the generic PP3 supporting threshold of 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history information is available to evaluate specificity for a single-gene disease.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions and no qualifying exact-variant reputable-source pathogenic report.	clinvar
BA1	Met	Met: gnomAD v4.1 grpmax FAF 0.407473 exceeds the 0.05 BA1 threshold in a South Asian group with 91,062 observed alleles.	gnomad_v4 gnomad_v2 clinvar
BS1	Met	Met strong: gnomAD v4.1 grpmax FAF 0.407473 is far above the generic BS1 0.01 threshold in a large ancestry sample.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports 76,973 homozygotes, but provides no individual age, phenotype, or documented healthy-adult status for BS2.	gnomad_v4 gnomad_v2
BS3	Met	Met at supporting: purified recombinant Glu429Ala MTHFR had wild-type biochemical properties, but other variant-specific assays reported reduced activity.	PMID:11742092 PMID:11752418 PMID:11395038 PMID:9545395
BS4	Not assessed	Not assessed: no affected relatives with discordant genotypes are documented, so family-level lack of segregation and the phenocopy caveat cannot be evaluated.	PMID:11590551
BP1	Not assessed	Not assessed: no curated MTHFR variant-spectrum evidence shows disease is caused primarily by truncating variants.	pvs1_gene_context
BP2	Not assessed	Not assessed: no data demonstrate c.1286A>C in trans with a fully penetrant dominant pathogenic allele or in cis with any pathogenic allele.	PMID:11590551
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting strength: REVEL 0.197 is at or below the generic BP4 supporting threshold of 0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no case documents this variant alongside a demonstrated alternate molecular basis for the disease.
BP6	Not met	Not met: benign ClinVar assertions are non-expert and conflicting, with zero exact-variant expert-panel submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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