The MEFV NM_000243.3:c.2080A>G (NP_000234.1:p.(Met694Val)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: M694V showed impaired cytokine suppression and caspase-1 binding in controlled cell assays and caused inflammatory disease in a knock-in mouse model. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic 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.MEFV encodes pyrin, a protein that helps regulate the body’s innate immune response. Changes in MEFV are associated with familial Mediterranean fever, an inherited condition causing recurrent episodes of fever and inflammation. MEFV has no established cancer-related role.
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: MEFV p.Met694Val is an established FMF-associated pathogenic missense change reported clinically and functionally in multiple studies.
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.
Met: M694 lies in the documented pyrin B30.2 functional interaction domain, where mutant pyrin showed substantially reduced caspase-1 binding.
Met: parental genotypes place M694V in trans with pathogenic V726A or M680I in affected FMF siblings, satisfying the recessive trans criterion at supporting strength.
Met: a different missense substitution at residue 694, p.Met694Ile, is reported among FMF-associated MEFV disease mutations.
Met at supporting strength: five affected grandchildren carried M694V-containing genotypes, although two older carriers were asymptomatic in the same family.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS1 and PS3 strong, plus PM1 and PM5 moderate and PM3 and PP1 supporting, satisfy the generic ACMG/AMP 2015 2-Strong rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 285 / 1,614,154 alleles. Recorded AF 0.000176563. Recorded homozygote count 3.
This variant is present in gnomAD v2.1 (AF= 0.000272204; MAF= 0.02722%, 77/282876 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 0.000968724; MAF= 0.09687%, 7/7226 alleles, homozygotes = 0); grpmax FAF= 0.00038139.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0009773048105114561, 18/18418 alleles, homozygotes = 0).
Recorded REVEL score: 0.406. Refer to the recorded PP3/BP4 rationale for interpretation.
52 Pathogenic · 2 pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
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: 6 met · 10 not met · 8 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS1 is met at strong strength because p.Met694Val is an established FMF-associated pathogenic missense change.
PM1 is met at moderate strength because residue 694 lies in the documented pyrin B30.2 functional interaction domain.
PM5 is met at moderate strength because p.Met694Ile is a different FMF-associated missense substitution at the same residue.
PP2 is not assessed because the required gene-wide low rate of benign missense variation is not documented.
BP1 is not met because the supplied evidence supports a missense-driven MEFV disease mechanism rather than primarily truncating disease causation.
The available evidence supports PP1 at supporting strength from multiple affected relatives carrying M694V-containing MEFV genotypes, but does not support PS2, PM6, or BS4.
Asymptomatic M694V-containing carriers and the autosomal-recessive genotype context reduce the specificity of segregation evidence and require human review of PP1.
PS3 is met at strong strength because three variant-specific, biologically relevant functional study lines show concordant loss of pyrin activity or inflammatory disease in controlled cell, biochemical, and knock-in mouse assays.
BS3 is not met because no reviewed functional study demonstrated preserved normal MEFV protein function or splicing.
PS4 was not assessed because a Turkish affected-versus-healthy comparison was verified, but the case frequency or counts needed to compute OR and 95% CI were unavailable.
PP4 was not assessed because the patient's phenotype and family history were not documented.
PP5 and BP6 were not met because the exact-variant ClinVar record has zero expert-panel submissions and no qualifying expert-panel classification.
BP5 was not assessed because no alternate molecular basis was documented for an M694V-positive case.
PM3 met at supporting strength: parental genotypes in PMID:11977178 place M694V in trans with V726A (siblings IV2, IV3, IV4, IV6) and with M680I (IV11), all affected with FMF; PMID:10787449 independently reports M694V and M680I on opposite MEFV alleles.
BP2 not met: the same phase data show trans rather than cis configuration, and MEFV/FMF is an autosomal recessive disorder with documented reduced penetrance, not a fully penetrant dominant gene/disorder.
No criteria match.
PS1 is met because the assessed variant is MEFV p.Met694Val (M694V), an established FMF-associated pathogenic missense change previously reported in multiple clinical studies and functional investigations. The variant is a missense SNV rather than a canonical splice-site change, so the protein-level comparison is applicable. PMID:10787449 describes M694V as a well-recognized FMF-associated genotype, PMID:11977178 reports M694V-containing genotypes segregating with FMF in a family, and PMID:16785446 directly studies M694V as an FMF-associated mutation with impaired pyrin function.
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.
PS3 is met at strong strength. Three independent functional lines directly evaluate MEFV p.M694V: (1) engineered-cell assays showed markedly impaired pyrin suppression of IL-8 in SW982 cells and significantly reduced suppression of IL-1β, IL-8, and TNF-α in LPS-stimulated THP-1 cells relative to wild-type pyrin, with IL-6 serving as a non-significant assay outcome; (2) GST pull-down assays showed substantially decreased binding of M694V pyrin to caspase-1 versus wild type, and M694V failed to inhibit IL-1β production above empty-vector control; and (3) an in vivo MefvM694V/M694V knock-in mouse model produced a reproducible inflammatory phenotype with growth retardation, wasting, dermatitis, and arthritis, together with constitutive inflammasome activation and IL-1β secretion. These variant-specific assays used wild-type, empty-vector, or comparator-mutant controls and measure biologically relevant pyrin inflammatory function, providing concordant evidence of a damaging effect.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM1 is met at moderate strength. No VCEP or authoritative domain table is present for MEFV, so the generic rule applies. M694 lies within the MEFV pyrin B30.2 domain, a documented functional interaction domain; PMID:16785446 places M694 within the modeled B30.2-caspase-1 interface and reports substantially reduced caspase-1 binding for mutant pyrin. The case hotspot search found no statistically significant somatic hotspot, so the domain route—not a cancer-hotspot route—is used. The available evidence does not establish a VCEP-specific restricted region or an alternate hotspot source requirement.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
MEFV c.2080A>G (p.Met694Val) is one of the established FMF-causing MEFV variants, and published family data place it in trans with a second pathogenic MEFV variant in affected individuals. In the inbred Arab family of PMID:11977178, four affected siblings (IV2, IV3, IV4, IV6) with FMF before age 10 are compound heterozygotes for V726A and M694V; their mother III2 is a silent V726A homozygote and their father III1 carries M694V, so the two variants must lie on opposite parental alleles. The affected cousin IV11 (recurrent abdominal pain from age 7, colchicine-responsive) is a compound heterozygote for M694V and M680I, with father III3 carrying M694V/V726A and mother III4 carrying M680I/K695R, again establishing trans phase. PMID:10787449 independently reports that M694V and M680I were 'encoded on opposite MEFV alleles in a Turkish family', determined by complete coding-sequence analysis with family testing. Both V726A and M680I are recognized FMF-causing MEFV variants, so the partner allele is pathogenic as PM3 requires. PMID:16785446 adds an affected patient with the M694V/M694V genotype and systemic amyloidosis, confirming that biallelic M694V is compatible with the FMF phenotype. The trans observation therefore rests on parental genotypes (the phase-testing the rule requires), not on inference from compound heterozygosity alone, and the criterion is met at supporting strength under the generic ACMG/AMP definition. Caveats: one M694V/M680I individual in the Turkish kindred of PMID:10787449 was asymptomatic, and several compound heterozygotes in PMID:11977178 (including M694V/V726A) never developed FMF, so reduced penetrance is documented; this does not alter the phase finding, since PM3 asks only for detection in trans with a pathogenic variant.
For recessive disorders, detected in trans with a pathogenic variant
PM5 is met because the assessed missense change is p.Met694Val and a different missense substitution at the same amino-acid residue, p.Met694Ile (M694I), has been reported as an FMF-associated disease mutation. PMID:11977178 lists M694I among the MEFV alterations accounting for the majority of FMF chromosomes and reports an affected individual with an M694V/M680I genotype; PMID:16785446 also identifies M694I among FMF-associated pyrin mutations. The assessed variant is a missense change and the evidence is being applied at the protein level rather than as a splice effect.
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.
PMID:11977178 reports an inbred family of 13 individuals in which four grandchildren with M694V/V726A and one with M694V/M680I had FMF; among nine grandchildren, only those with an M694V-containing genotype were symptomatic. This supports cosegregation of M694V with disease in multiple affected relatives, but the asymptomatic father and grandmother carrying M694V/V726A and the autosomal-recessive genotype context limit interpretation to supporting strength and warrant human review.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
PM2 is not met. The variant is observed in population controls at AF 0.000176563 in gnomAD v4.1 overall (285/1614154), 0.000272204 in gnomAD v2.1 overall (77/282876), 0.000286978 in gnomAD v2.1 non-cancer exomes (68/236952), and 0.000121699 in gnomAD v3.1 non-cancer genomes (18/147906). Each exceeds the supplied generic PM2 supporting threshold of <=0.0001.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
PP3 is applicable because NM_000243.3:c.2080A>G is a missense variant, so the governing rule requires the missense REVEL path only; SpliceAI is not used for this missense PP3 assessment. REVEL is 0.406, below the generic supporting PP3 threshold of >= 0.644 calibrated by ClinGen SVI (Pejaver et al. 2022, PMID:36413997). BayesDel is not counted because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3/BP4 take evidence from exactly ONE path, selected by the variant's own consequence type, never from both. ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
ClinVar contains exact-variant pathogenic and likely pathogenic laboratory submissions, but the exact-variant record reports zero expert-panel submissions. Under the specified generic rule, ordinary laboratory submissions, aggregate ClinVar labels, and published case reports do not trigger PP5; no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The highest observed population frequency is 0.00461894 (28/6062 alleles; Middle Eastern, gnomAD v4.1), which is below the ACMG/AMP stand-alone threshold of 0.05. The overall gnomAD v4.1 frequency is 0.000176563 (285/1614154), and the gnomAD v2.1 non-cancer exome frequency is 0.000286978 (68/236952).
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. The highest observed frequency is 0.00461894 in the Middle Eastern population, below the generic 0.01 default. FMF is recessive, has high ancestry-specific carrier frequencies, and incomplete penetrance is documented; therefore the frequency does not establish that this allele is greater than expected for the disorder. No maximum-credible-frequency calculation is needed to apply BS1 because the observed frequency does not reach the default threshold.
Allele frequency is greater than expected for disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS3 is not met. The available variant-specific functional evidence is damaging rather than neutral: M694V showed impaired cytokine suppression and reduced caspase-1 binding in controlled cell assays, and MefvM694V/M694V knock-in mice developed inflammatory disease. No well-established assay demonstrated absence of a damaging effect on protein function or splicing.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP1 is not met because MEFV is not characterized here as a gene in which disease is caused primarily by truncating variants. Instead, the supplied clinical and experimental evidence repeatedly identifies missense MEFV mutations, including M694V, M694I, M680I, and V726A, as disease-associated and demonstrates inflammatory effects from missense pyrin mutations. Therefore the gene-level premise of BP1 is not satisfied.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 requires either trans-phase observation in a fully penetrant dominant gene/disorder, or cis-phase observation with a pathogenic variant under any inheritance pattern. Neither arm is satisfied. FMF due to MEFV is an autosomal recessive disorder (PMID:10787449, PMID:11977178), and the published families show reduced penetrance rather than full penetrance: in PMID:11977178 the asymptomatic mother III2 is a V726A homozygote, the asymptomatic father III3 carries M694V/V726A, and four of nine compound-heterozygous grandchildren had no disease signs; PMID:10787449 describes an individual with the well-recognized FMF-associated M694V/M680I genotype who never experienced symptoms. MEFV therefore cannot be treated as a fully penetrant dominant gene and the dominant arm of BP2 does not apply. For the cis arm, the phase data point the other way: M694V was found on the opposite allele from V726A and from M680I in the families of PMID:11977178 and PMID:10787449, i.e. in trans, not in cis. No report in the reviewed evidence places M694V in cis with a pathogenic MEFV variant. BP2 is therefore applicable and not met.
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.
BP4 is applicable because NM_000243.3:c.2080A>G is a missense variant, so the governing rule requires the missense REVEL path only; the SpliceAI result cannot substitute for a gray-zone REVEL result. REVEL is 0.406, above the generic BP4 supporting threshold of <= 0.29, so BP4 is not met. BayesDel is not counted 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). ... PP3/BP4 take evidence from exactly ONE path, selected by the variant's own consequence type, never from both. ... Missense variant -> REVEL only. ... A gray-zone REVEL result means BP4 is not met; it does not license substituting the SpliceAI score. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
ClinVar reports zero exact-variant expert-panel submissions and no expert-panel benign or likely benign classification. The available laboratory submissions are pathogenic or likely pathogenic, and no exact-variant ClinVar expert-panel benign report was identified; these findings do not 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.
No case-specific evidence establishes that the MEFV c.2080A>G (p.Met694Val) variant arose de novo. The available family literature describes inherited M694V-containing genotypes and does not document confirmed maternity and paternity for a proband with no family history.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The literature_pass packet identified PMID:11464248 as a PS4 candidate and its abstract verifies a genuine affected-versus-healthy comparison: mutation frequency was measured in clinically diagnosed FMF patients and carrier frequency in healthy Turkish individuals, with M694V reported in 3% of healthy individuals. The abstract does not provide the corresponding affected-patient count or frequency, and no verified case/control counts or reported odds ratio with 95% confidence interval are available in the reviewed evidence. PMID:10364520 is a 90-patient Armenian FMF case series, not a case-control comparison; PMID:10787449 reports affected families and incomplete penetrance but does not provide the required matched control comparison. Therefore an OR and 95% CI cannot be computed and the PS4 threshold cannot be adjudicated. The governing comparison is OR >5.0 with a confidence interval that does not include 1.0; no numeric OR/CI is available for the explicit inequality.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... 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.
No case-specific evidence establishes an assumed de novo MEFV c.2080A>G (p.Met694Val) variant. The available family literature describes inherited M694V-containing genotypes and does not provide a proband-parent comparison showing the variant absent from tested parents.
Assumed de novo, but without confirmation of paternity and maternity.
PP2 cannot be assessed from the available evidence because the case documents a missense-driven MEFV disease mechanism but does not provide a gene-wide analysis demonstrating a low rate of benign missense variation. Functional and clinical reports of M694V establish variant-level disease association, not the required gene-level benign-missense rate.
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 case evidence does not document this patient's clinical phenotype, diagnostic findings, or family history. Literature about FMF manifestations and M694V genotype-phenotype relationships cannot substitute for case-specific phenotype documentation, so it is not possible to determine whether the presentation is highly specific for a disease with a single genetic etiology.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available population counts alone. gnomAD reports three homozygotes in v4.1 overall, including two in the Middle Eastern population, and one homozygote in gnomAD v2.1 non-cancer exomes, but these records do not establish that the individuals were healthy adults phenotyped for FMF or had full penetrance expected at an early age. A healthy-adult phenotype review for the identified homozygotes is required.
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.
No evidence identifies affected family members who lack MEFV c.2080A>G (p.Met694Val). The available family study instead reports affected individuals with M694V-containing genotypes and asymptomatic carriers, which is not lack of segregation in affected members and cannot establish BS4.
Lack of segregation in affected members of a family. ... Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals.
No reviewed source documents an M694V-positive patient who also had an independently established alternate molecular diagnosis explaining the disease. The available literature describes MEFV-associated FMF, family segregation, functional findings, and population frequencies, but does not establish the alternate molecular basis required for BP5.
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_000243.3:c.2080A>G in MEFV is a missense substitution predicted to produce NP_000234.1:p.(Met694Val). 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 MEFV, 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_000243.3:c.2080A>G in MEFV is a missense substitution predicted to produce NP_000234.1:p.(Met694Val). 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 MEFV, 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_000243.3:c.2080A>G in MEFV is a missense substitution predicted to produce NP_000234.1:p.(Met694Val). 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 MEFV, 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_000243.3:c.2080A>G in MEFV is a missense substitution predicted to produce NP_000234.1:p.(Met694Val). 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 MEFV, 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 MEFV, mapped onto the exon structure of NM_000243.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Middle Eastern28 / 6,062 | 0.00462 hom |
| Remaining individuals58 / 62,512 | 0.000931 hom |
| Admixed American14 / 60,026 | 0.00023 |
| European (non-Finnish)179 / 1,180,014 | 0.00015 |
| African/African American4 / 75,030 | 5.3e-05 |
| Ashkenazi Jewish1 / 29,608 | 3.4e-05 |
| South Asian1 / 91,082 | 1.1e-05 |
| Remaining individuals7 / 7,226 | 0.00097 |
| European (non-Finnish)59 / 129,184 | 0.000461 hom |
| Admixed American9 / 35,438 | 0.00025 |
| African/African American2 / 24,968 | 8e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000176563; MAF= 0.01766%, 285/1614154 alleles, homozygotes = 3) and has highest observed frequency in the Middle Eastern population (AF= 0.00461894; MAF= 0.46189%, 28/6062 alleles, homozygotes = 2); grpmax FAF= 0.0032822.
This variant is present in gnomAD v2.1 (AF= 0.000272204; MAF= 0.02722%, 77/282876 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 0.000968724; MAF= 0.09687%, 7/7226 alleles, homozygotes = 0); grpmax FAF= 0.00038139.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0009773048105114561, 18/18418 alleles, homozygotes = 0).
PP3 is applicable because NM_000243.3:c.2080A>G is a missense variant, so the governing rule requires the missense REVEL path only; SpliceAI is not used for this missense PP3 assessment. REVEL is 0.406, below the generic supporting PP3 threshold of >= 0.644 calibrated by ClinGen SVI (Pejaver et al. 2022, PMID:36413997). BayesDel is not counted because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3/BP4 take evidence from exactly ONE path, selected by the variant's own consequence type, never from both. ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP4 is applicable because NM_000243.3:c.2080A>G is a missense variant, so the governing rule requires the missense REVEL path only; the SpliceAI result cannot substitute for a gray-zone REVEL result. REVEL is 0.406, above the generic BP4 supporting threshold of <= 0.29, so BP4 is not met. BayesDel is not counted 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). ... PP3/BP4 take evidence from exactly ONE path, selected by the variant's own consequence type, never from both. ... Missense variant -> REVEL only. ... A gray-zone REVEL result means BP4 is not met; it does not license substituting the SpliceAI score. ... BP4 (supporting): <= 0.29 — 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_000243.3:c.2080A>G in MEFV is a missense substitution predicted to produce NP_000234.1:p.(Met694Val). 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 MEFV, 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 = 0.00). REVEL score = 0.406. BayesDel score = 0.0157936.
11 paper records listed. 5 cited in the classification.
Pyrin E148Q and M694I were encoded on opposite MEFV alleles in a Jordanian family, as were M694V and M680I in a Turkish family. One individual in the latter kindred had this well-recognized FMF-associated genotype without ever having experienced symptoms, indicating incomplete penetrance.
Location Results, first paragraph; Discussion, paragraph discussing the importance of methionine 694
Context MEFV genotyping and sequencing in five families with family-member testing and review of additional patients.
Of nine grandchildren who were compound heterozygotes for two mutations in the MEFV gene, only those with either the M694V/V726A or the M694V/M680I genotypes manifested the disease
Location Abstract; Subjects; Table I; Phenotype-Genotype Correlation
Context Clinical and segregation study of 13 members of one inbred family using PCR-based MEFV mutation analysis and standardized FMF criteria.
The binding of caspase-1 to the mutants was substantially decreased, relative to WT pyrin, as shown on Western blots and corresponding densitometry.
Location Results, “Interaction of Caspase-1 with Pyrin Constructs Harboring FMF-Associated Mutations”; “A Model for the Interaction of Pyrin with Caspase-1”
Context GST pull-down and Western blot assays with wild-type and FMF-associated pyrin constructs, cell-based IL-1β assays, computational docking, and a clinical observation of M694V homozygosity.
milder but detectable illness developed after more than 20 weeks birth for MefvM694V/M694V mice, with growth retardation, wasting, dermatitis, and arthritis
Location Results, “Insertion of FMF-associated mutant B30.2 domains induces inflammation in mice,” paragraph 2
Context In vivo homozygous and heterozygous MEFV B30.2-domain knock-in mouse models with inflammatory, cytokine, inflammasome, and genetic-cross experiments.
pyrin-M694V hardly suppressed IL-8 secretion from SW982 and THP-1 cells
Location Results, IL-8 secretion experiments in SW982 and THP-1 cells; Discussion
Context Site-specific M694V pyrin expression in SW982, HEK293T, and stable THP-1 cells with cytokine ELISA after LPS stimulation.
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= 0.000176563; MAF= 0.01766%, 285/1614154 alleles, homozygotes = 3) and has highest observed frequency in the Middle Eastern population (AF= 0.00461894; MAF= 0.46189%, 28/6062 alleles, homozygotes = 2); grpmax FAF= 0.0032822.
This variant is present in gnomAD v2.1 (AF= 0.000272204; MAF= 0.02722%, 77/282876 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 0.000968724; MAF= 0.09687%, 7/7226 alleles, homozygotes = 0); grpmax FAF= 0.00038139.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0009773048105114561, 18/18418 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Pathogenic (52 clinical laboratories) and as pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 2538)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.406. BayesDel score = 0.0157936.
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.