LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-29
Case ID: NM_000243.3_c.2080A_G_20261029_161527
Framework: ACMG/AMP 2015
Variant classification summary

NM_000243.3:c.2080A>G

MEFV  · NP_000234.1:p.(Met694Val)  · NM_000243.3
GRCh37: chr16:3293407 T>C  ·  GRCh38: chr16:3243407 T>C
Gene: MEFV Transcript: NM_000243.3
Final call
Pathogenic
PS1 strong PS3 strong PM1 moderate PM3 supporting PM5 moderate PP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MEFV
Transcript
NM_000243.3
Protein
NP_000234.1:p.(Met694Val)
gnomAD AF
0.00017656307886360285 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS1 strong supports the established pathogenicity of MEFV p.Met694Val.
2
Pathogenic: PS3 strong shows damaging M694V effects in controlled functional and knock-in mouse studies.
3
Pathogenic: PM1 moderate places residue 694 in the functional pyrin B30.2 domain.
4
Pathogenic: PM3 supporting documents M694V in trans with pathogenic MEFV variants in affected individuals.
5
Pathogenic: PM5 moderate identifies pathogenic p.Met694Ile at the same residue.
6
Pathogenic: PP1 supporting shows M694V-containing genotypes in multiple affected relatives.
Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria satisfy the Pathogenic classification rule; additional moderate and supporting pathogenic criteria reinforce the call.
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 Met Met: MEFV p.Met694Val is an established FMF-associated pathogenic missense change reported clinically and functionally in multiple studies.
PMID:10787449 PMID:11977178 PMID:16785446 clinvar
PS2 Not assessed Not assessed: no case-specific evidence confirms de novo origin with both maternity and paternity confirmed and no family history.
PS3 Met Met, strong: M694V showed impaired cytokine suppression and caspase-1 binding in controlled cell assays and caused inflammatory disease in a knock-in mouse model.
PMID:24318677 PMID:16785446 PMID:21600797
PS4 Not assessed Not assessed: a Turkish patient-control comparison was verified, but missing affected-case counts prevent calculating the required OR >5.0 and confidence interval excluding 1.0.
PMID:10787449
PM1 Met Met: M694 lies in the documented pyrin B30.2 functional interaction domain, where mutant pyrin showed substantially reduced caspase-1 binding.
PMID:16785446 hotspots
PM2 Not met Not met: gnomAD v4.1 overall AF is 0.000176563, above the PM2 supporting threshold of <=0.0001.
gnomad_v2 gnomad_v4
PM3 Met Met: parental genotypes place M694V in trans with pathogenic V726A or M680I in affected FMF siblings, satisfying the recessive trans criterion at supporting strength.
PMID:11977178 PMID:10787449 PMID:16785446
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 Met Met: a different missense substitution at residue 694, p.Met694Ile, is reported among FMF-associated MEFV disease mutations.
PMID:11977178 PMID:16785446
PM6 Not assessed Not assessed: no case-specific evidence shows an assumed de novo variant with parental testing information.
PP1 Met Met at supporting strength: five affected grandchildren carried M694V-containing genotypes, although two older carriers were asymptomatic in the same family.
PMID:11977178 PMID:10787449
PP2 Not assessed Not assessed: MEFV missense disease mechanism is documented, but no gene-wide benign-missense rate is available for the PP2 requirement.
PMID:21600797 PMID:24318677
PP3 Not met Not met: REVEL 0.406 is below the generic PP3 supporting threshold of 0.644 for this missense variant.
revel
PP4 Not assessed Not assessed: the patient's phenotype and family history are undocumented, so specificity for a single genetic etiology cannot be judged.
PMID:11977178
PP5 Not met Not met: the exact variant has 0 ClinVar expert-panel submissions, so laboratory pathogenic assertions cannot trigger PP5 under the specified rule.
clinvar
BA1 Not met Not met: the highest observed allele frequency is 0.00461894, below the BA1 threshold of 0.05.
gnomad_v2 gnomad_v4
BS1 Not met Not met: the highest observed allele frequency is 0.00461894, below the generic BS1 default of 0.01.
gnomad_v2 gnomad_v4 PMID:10787449
BS2 Not assessed Not assessed: gnomAD reports three homozygotes, but no evidence confirms they were healthy adults without early-onset FMF.
gnomad_v2 gnomad_v4 PMID:10787449
BS3 Not met Not met: M694V impaired cytokine suppression and caspase-1 binding, while knock-in mice developed inflammation; no neutral functional assay result was reported.
PMID:24318677 PMID:16785446 PMID:21600797
BS4 Not assessed Not assessed: no affected family member is documented to lack the variant, the required evidence for lack of segregation.
PMID:11977178
BP1 Not met Not met: MEFV disease evidence centers on multiple pathogenic missense mutations and missense-driven inflammatory effects, not primarily truncating variants.
PMID:11977178 PMID:16785446 PMID:21600797
BP2 Not met Not met: M694V is in trans, not cis, with pathogenic MEFV variants (V726A, M680I), and recessive, reduced-penetrance FMF is not a fully penetrant dominant disorder.
PMID:11977178 PMID:10787449
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 Not met Not met: REVEL 0.406 is above the generic BP4 supporting threshold of 0.29 for this missense variant.
revel
BP5 Not assessed Not assessed: no M694V-positive case was documented with an independent alternate molecular diagnosis explaining the disease.
BP6 Not met Not met: ClinVar has 0 exact-variant expert-panel submissions and no expert-panel benign or likely benign classification to trigger BP6.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.