Published functional studies demonstrate that M694I alters the level of IL8 secretion in vitro (Sugiyama et al., 2014); This variant is associated with the following publications: (PMID: 26413094, 26399837, 27150194, 26400644, 25393764, 25286988, 25449140, 25528861, 26003477, 24286006, 23907647, 21727109, 10090880, 19863562, 11938447, 12924509, 10787449, 11175300, 26299986, 24318677, 24533546, 26074413, 26173767, 15942916, 22975760, 24593212, 22766764, 20051664, 15168590, 23461592, 15805719, 12064853, 27181238, 16704654, 19480334, 9288094, 17711558, 16730661, 16378925, 10612841, 10234504, 10024914, 29543225, 28828621, 32199921, 29080837, 31589614, 33440462, 10842289, 10852276, 10662876)
ClinVar Genomic variation as it relates to human health
NM_000243.3(MEFV):c.2082G>A (p.Met694Ile)
Germline
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.
(36)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
36
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Haplotype
- Identifiers
-
NM_000243.3(MEFV):c.2082G>A (p.Met694Ile)
Variation ID: 2539 Accession: VCV000002539.103
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.3 16: 3243405 (GRCh38) [ NCBI UCSC ] 16: 3293405 (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 Apr 4, 2013 Oct 20, 2024 Jul 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000243.3:c.2082G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000234.1:p.Met694Ile missense NM_001198536.2:c.*286G>A 3 prime UTR NC_000016.10:g.3243405C>T NC_000016.9:g.3293405C>T NG_007871.1:g.18223G>A LRG_190:g.18223G>A LRG_190t1:c.2082G>A LRG_190p1:p.Met694Ile O15553:p.Met694Ile - Protein change
- -
- Other names
-
M694I
- Canonical SPDI
- NC_000016.10:3243404:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00014
Exome Aggregation Consortium (ExAC) 0.00015
- Links
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. |
|||
| MEFV | No evidence available | No evidence available |
GRCh38 GRCh37 |
957 | 1258 | |
| LOC126862264 | - | - | - | GRCh38 | - | 257 |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (15) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2024 | RCV000002648.36 | |
| Pathogenic (14) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV000220431.58 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV000589706.14 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 4, 2020 | RCV000763380.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 25, 2022 | RCV002262540.10 | |
|
MEFV-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 13, 2024 | RCV004528066.2 |
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. |
More information
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 22, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280932.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
|
|
|
Pathogenic
(Jun 25, 2017)
|
criteria provided, single submitter
Method: research
|
Familial Mediterranean fever, autosomal dominant
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Study: Broad Institute Center for Mendelian Genomics (CMG)
Accession: SCV000693895.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Number of individuals with the variant: 2
Clinical Features:
Nephrotic syndrome (present)
|
|
|
Pathogenic
(Oct 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000854900.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Jun 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000279059.8
First in ClinVar: May 29, 2016 Last updated: Oct 09, 2016 |
Comment:
Published functional studies demonstrate that M694I alters the level of IL8 secretion in vitro (Sugiyama et al., 2014); This variant is associated with the following … (more)
Published functional studies demonstrate that M694I alters the level of IL8 secretion in vitro (Sugiyama et al., 2014); This variant is associated with the following publications: (PMID: 26413094, 26399837, 27150194, 26400644, 25393764, 25286988, 25449140, 25528861, 26003477, 24286006, 23907647, 21727109, 10090880, 19863562, 11938447, 12924509, 10787449, 11175300, 26299986, 24318677, 24533546, 26074413, 26173767, 15942916, 22975760, 24593212, 22766764, 20051664, 15168590, 23461592, 15805719, 12064853, 27181238, 16704654, 19480334, 9288094, 17711558, 16730661, 16378925, 10612841, 10234504, 10024914, 29543225, 28828621, 32199921, 29080837, 31589614, 33440462, 10842289, 10852276, 10662876) (less)
|
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318549.1
First in ClinVar: Apr 11, 2022 Last updated: Apr 11, 2022 |
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10612841, 16378925). he variant has been reported to be in trans with … (more)
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10612841, 16378925). he variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 16378925) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 12064853). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001427). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002538,VCV000449657, PMID:23031807,NULL,9288758). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Infectious encephalitis (present) , Meningitis (present) , Oral ulcer (present) , Recurrent infections (present) , Vasculitis (present)
|
|
|
Pathogenic
(Mar 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002543733.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
|
|
|
Pathogenic
(Jul 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577426.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PS3, PM1, PM5, PM2, PP5, BP4
|
|
|
Pathogenic
(Apr 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579057.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4, PM3, PM5, PM2_SUP, PP1
|
Number of individuals with the variant: 2
Sex: male
|
|
|
Pathogenic
(Feb 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761344.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
|
Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139823.2
First in ClinVar: Jan 09, 2020 Last updated: Apr 01, 2023 |
|
|
|
Likely pathogenic
(May 08, 2023)
|
criteria provided, single submitter
Method: research
|
Familial Mediterranean fever
Affected status: yes
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV003924343.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
|
|
|
Pathogenic
(Sep 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045786.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Recurrent fever (present) , Vasculitis (present) , Abnormal coagulation factor V activity (present) , Episodic abdominal pain (present)
|
|
|
Pathogenic
(Feb 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226902.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PM1, PM3_very_strong, PM5, PS3, PS4
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017259.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Dec 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604182.10
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The MEFV c.2082G>A;p.Met694Ile variant (rs28940578) is reported as a common familial Mediterranean fever (FMF) pathogenic variant (Majeed 2005, Moradian 2014). The variant is listed in … (more)
The MEFV c.2082G>A;p.Met694Ile variant (rs28940578) is reported as a common familial Mediterranean fever (FMF) pathogenic variant (Majeed 2005, Moradian 2014). The variant is listed in the ClinVar database (Variation ID: 2539). This variant is found in the general population with an overall allele frequency of 0.01% (36/282886 alleles) in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. References: Majeed HA et al. The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum. 2005. 34(6):813-8. PMID: 15942916 Moradian MM et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 16(3):258-63. PMID: 23907647 (less)
|
|
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Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000933995.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 694 of the MEFV protein (p.Met694Ile). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 694 of the MEFV protein (p.Met694Ile). This variant is present in population databases (rs28940578, gnomAD 0.05%). This missense change has been observed in individuals with familial Mediterranean fever (PMID: 10787449, 12064853, 15168590, 15805719, 20051664). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2539). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects MEFV function (PMID: 24318677). This variant disrupts the p.Met694 amino acid residue in MEFV. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9781020, 10364520, 12064853, 21290976, 22037353). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847546.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Met694Ile variant in MEFV is one of the most commonly reported pathogenic variant (both in the homozygous and compound heterozygous state) in individuals with … (more)
The p.Met694Ile variant in MEFV is one of the most commonly reported pathogenic variant (both in the homozygous and compound heterozygous state) in individuals with familial Mediterranean fever (examples: Majeed 2005 PMID: 15942916, Moradian 2014 PMID: 23907647). It has been reported in ClinVar ( Variation ID 2539) and has been identified in 1/316 Middle Eastern and 3/5196 East Asian chromosomes (among other population where the variant freqency is lower) by gnomAD ((http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant affects the level of IL8 secretion (Sugiyama 2014 PMID: 24318677). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive familial Mediterranean fever. ACMG/AMP Criteria applied: PM2_Supporting, PM3_VeryStrong, PS3_Supporting. (less)
|
|
|
Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245669.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
MEFV: PM3:Very Strong, PM1, PM5, PM2:Supporting, PS3:Supporting, BP4
Number of individuals with the variant: 27
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever, autosomal dominant
Familial Mediterranean fever
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894079.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Oct 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever, autosomal dominant
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000898824.2
First in ClinVar: Apr 25, 2019 Last updated: Jul 15, 2019 |
Comment:
MEFV NM_000243.2 exon 10 p.Met694Ile (c.2082G>A): This variant is one of the most common pathogenic mutations associated with Familial Mediterranian Fever. This variant has been … (more)
MEFV NM_000243.2 exon 10 p.Met694Ile (c.2082G>A): This variant is one of the most common pathogenic mutations associated with Familial Mediterranian Fever. This variant has been reported in several publications, including a GeneReviews entry describing this variant as disease causing (Shothat 2016 PMID:20301405). This variant is present in 17/12674 European individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28940578). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:2539). In summary, this variant is classified as pathogenic based on the data above. (less)
|
|
|
Pathogenic
(Dec 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193934.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000243.2(MEFV):c.2082G>A(M694I) is classified as pathogenic in the context of familial Mediterranean fever. Please note that in the absence of a known personal and/or family history … (more)
NM_000243.2(MEFV):c.2082G>A(M694I) is classified as pathogenic in the context of familial Mediterranean fever. Please note that in the absence of a known personal and/or family history of inflammatory disease, the clinical significance of this MEFV variant status is uncertain. Sources cited for classification include the following: PMID 9288094, 10612841, 16378925, 19863562, 11938447, and 16378925. Classification of NM_000243.2(MEFV):c.2082G>A(M694I) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Oct 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever, autosomal dominant
Familial Mediterranean fever
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001448271.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
Sex: male
|
|
|
Pathogenic
(Dec 18, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450267.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 12
|
|
|
Pathogenic
(Feb 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001480074.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Clinical Features:
Recurrent fever (present)
Sex: female
|
|
|
pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation, clinical testing
|
Familial Mediterranean Fever
(autosomal recessive)
Affected status: yes, unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052841.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 55
Observation 2:
Tissue: Blood
Observation 3:
Tissue: Blood
|
|
|
Pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Mediterranean fever, autosomal dominant
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194405.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jun 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198750.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Sep 01, 1997)
|
no assertion criteria provided
Method: literature only
|
FAMILIAL MEDITERRANEAN FEVER
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022806.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 15, 2020 |
Comment on evidence:
In an Arabian family with familial Mediterranean fever (FMF; 249100), the French FMF Consortium (1997) found that affected members bearing an ARA2 haplotype had a … (more)
In an Arabian family with familial Mediterranean fever (FMF; 249100), the French FMF Consortium (1997) found that affected members bearing an ARA2 haplotype had a 1172G-A transition in their partial MEFV cDNA sequence, resulting in a met694-to-ile (M694I) substitution. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001462097.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929663.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951693.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001976076.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(May 13, 2024)
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no assertion criteria provided
Method: clinical testing
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MEFV-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004107584.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The MEFV c.2082G>A variant is predicted to result in the amino acid substitution p.Met694Ile. This variant has previously been reported to be causative for familial … (more)
The MEFV c.2082G>A variant is predicted to result in the amino acid substitution p.Met694Ile. This variant has previously been reported to be causative for familial Mediterranean fever (Gershoni-Baruch et al. 2002. PubMed ID: 11938447; Moradian et al. 2014. PubMed ID: 23907647; Cazeneuve et al. 1999. PubMed ID: 10364520). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798514.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial Mediterranean fever
Affected status: yes
Allele origin:
unknown
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Genomics And Bioinformatics Analysis Resource, Columbia University
Accession: SCV004024082.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023
Comment:
Compound Heterozygous
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not provided
(-)
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no classification provided
Method: literature only
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Familial Mediterranean fever
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000484970.2
First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022 |
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Comment:
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10612841, 16378925). he variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 16378925) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 12064853). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001427). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002538,VCV000449657, PMID:23031807,NULL,9288758). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PS3, PM1, PM5, PM2, PP5, BP4
Comment:
PP1, PM1, PM3_very_strong, PM5, PS3, PS4
Comment:
The MEFV c.2082G>A;p.Met694Ile variant (rs28940578) is reported as a common familial Mediterranean fever (FMF) pathogenic variant (Majeed 2005, Moradian 2014). The variant is listed in the ClinVar database (Variation ID: 2539). This variant is found in the general population with an overall allele frequency of 0.01% (36/282886 alleles) in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. References: Majeed HA et al. The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum. 2005. 34(6):813-8. PMID: 15942916 Moradian MM et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 16(3):258-63. PMID: 23907647
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 694 of the MEFV protein (p.Met694Ile). This variant is present in population databases (rs28940578, gnomAD 0.05%). This missense change has been observed in individuals with familial Mediterranean fever (PMID: 10787449, 12064853, 15168590, 15805719, 20051664). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2539). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects MEFV function (PMID: 24318677). This variant disrupts the p.Met694 amino acid residue in MEFV. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9781020, 10364520, 12064853, 21290976, 22037353). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Met694Ile variant in MEFV is one of the most commonly reported pathogenic variant (both in the homozygous and compound heterozygous state) in individuals with familial Mediterranean fever (examples: Majeed 2005 PMID: 15942916, Moradian 2014 PMID: 23907647). It has been reported in ClinVar ( Variation ID 2539) and has been identified in 1/316 Middle Eastern and 3/5196 East Asian chromosomes (among other population where the variant freqency is lower) by gnomAD ((http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant affects the level of IL8 secretion (Sugiyama 2014 PMID: 24318677). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive familial Mediterranean fever. ACMG/AMP Criteria applied: PM2_Supporting, PM3_VeryStrong, PS3_Supporting.
Comment:
MEFV: PM3:Very Strong, PM1, PM5, PM2:Supporting, PS3:Supporting, BP4
Comment:
MEFV NM_000243.2 exon 10 p.Met694Ile (c.2082G>A): This variant is one of the most common pathogenic mutations associated with Familial Mediterranian Fever. This variant has been reported in several publications, including a GeneReviews entry describing this variant as disease causing (Shothat 2016 PMID:20301405). This variant is present in 17/12674 European individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28940578). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:2539). In summary, this variant is classified as pathogenic based on the data above.
Comment:
NM_000243.2(MEFV):c.2082G>A(M694I) is classified as pathogenic in the context of familial Mediterranean fever. Please note that in the absence of a known personal and/or family history of inflammatory disease, the clinical significance of this MEFV variant status is uncertain. Sources cited for classification include the following: PMID 9288094, 10612841, 16378925, 19863562, 11938447, and 16378925. Classification of NM_000243.2(MEFV):c.2082G>A(M694I) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Converted during submission to Pathogenic.
Comment:
The MEFV c.2082G>A variant is predicted to result in the amino acid substitution p.Met694Ile. This variant has previously been reported to be causative for familial Mediterranean fever (Gershoni-Baruch et al. 2002. PubMed ID: 11938447; Moradian et al. 2014. PubMed ID: 23907647; Cazeneuve et al. 1999. PubMed ID: 10364520). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Published functional studies demonstrate that M694I alters the level of IL8 secretion in vitro (Sugiyama et al., 2014); This variant is associated with the following publications: (PMID: 26413094, 26399837, 27150194, 26400644, 25393764, 25286988, 25449140, 25528861, 26003477, 24286006, 23907647, 21727109, 10090880, 19863562, 11938447, 12924509, 10787449, 11175300, 26299986, 24318677, 24533546, 26074413, 26173767, 15942916, 22975760, 24593212, 22766764, 20051664, 15168590, 23461592, 15805719, 12064853, 27181238, 16704654, 19480334, 9288094, 17711558, 16730661, 16378925, 10612841, 10234504, 10024914, 29543225, 28828621, 32199921, 29080837, 31589614, 33440462, 10842289, 10852276, 10662876)
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10612841, 16378925). he variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 16378925) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 12064853). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001427). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002538,VCV000449657, PMID:23031807,NULL,9288758). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PS3, PM1, PM5, PM2, PP5, BP4
Comment:
PP1, PM1, PM3_very_strong, PM5, PS3, PS4
Comment:
The MEFV c.2082G>A;p.Met694Ile variant (rs28940578) is reported as a common familial Mediterranean fever (FMF) pathogenic variant (Majeed 2005, Moradian 2014). The variant is listed in the ClinVar database (Variation ID: 2539). This variant is found in the general population with an overall allele frequency of 0.01% (36/282886 alleles) in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. References: Majeed HA et al. The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum. 2005. 34(6):813-8. PMID: 15942916 Moradian MM et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 16(3):258-63. PMID: 23907647
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 694 of the MEFV protein (p.Met694Ile). This variant is present in population databases (rs28940578, gnomAD 0.05%). This missense change has been observed in individuals with familial Mediterranean fever (PMID: 10787449, 12064853, 15168590, 15805719, 20051664). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2539). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects MEFV function (PMID: 24318677). This variant disrupts the p.Met694 amino acid residue in MEFV. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9781020, 10364520, 12064853, 21290976, 22037353). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Met694Ile variant in MEFV is one of the most commonly reported pathogenic variant (both in the homozygous and compound heterozygous state) in individuals with familial Mediterranean fever (examples: Majeed 2005 PMID: 15942916, Moradian 2014 PMID: 23907647). It has been reported in ClinVar ( Variation ID 2539) and has been identified in 1/316 Middle Eastern and 3/5196 East Asian chromosomes (among other population where the variant freqency is lower) by gnomAD ((http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant affects the level of IL8 secretion (Sugiyama 2014 PMID: 24318677). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive familial Mediterranean fever. ACMG/AMP Criteria applied: PM2_Supporting, PM3_VeryStrong, PS3_Supporting.
Comment:
MEFV: PM3:Very Strong, PM1, PM5, PM2:Supporting, PS3:Supporting, BP4
Comment:
MEFV NM_000243.2 exon 10 p.Met694Ile (c.2082G>A): This variant is one of the most common pathogenic mutations associated with Familial Mediterranian Fever. This variant has been reported in several publications, including a GeneReviews entry describing this variant as disease causing (Shothat 2016 PMID:20301405). This variant is present in 17/12674 European individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28940578). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:2539). In summary, this variant is classified as pathogenic based on the data above.
Comment:
NM_000243.2(MEFV):c.2082G>A(M694I) is classified as pathogenic in the context of familial Mediterranean fever. Please note that in the absence of a known personal and/or family history of inflammatory disease, the clinical significance of this MEFV variant status is uncertain. Sources cited for classification include the following: PMID 9288094, 10612841, 16378925, 19863562, 11938447, and 16378925. Classification of NM_000243.2(MEFV):c.2082G>A(M694I) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Converted during submission to Pathogenic.
Comment:
The MEFV c.2082G>A variant is predicted to result in the amino acid substitution p.Met694Ile. This variant has previously been reported to be causative for familial Mediterranean fever (Gershoni-Baruch et al. 2002. PubMed ID: 11938447; Moradian et al. 2014. PubMed ID: 23907647; Cazeneuve et al. 1999. PubMed ID: 10364520). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The PRY/SPRY domain of pyrin/TRIM20 interacts with β(2)-microglobulin to promote inflammasome formation. | Samukawa S | Scientific reports | 2021 | PMID: 34880353 |
| Rapid Flow Cytometry-Based Assay for the Functional Classification of MEFV Variants. | Honda Y | Journal of clinical immunology | 2021 | PMID: 33733382 |
| The association of MEFV gene mutations with the disease risk and severity of systemic juvenile idiopathic arthritis. | Zhong L | Pediatric rheumatology online journal | 2020 | PMID: 32398039 |
| Association between sequence variations of the Mediterranean fever gene and the risk of migraine: a case-control study. | Coşkun S | Neuropsychiatric disease and treatment | 2016 | PMID: 27621632 |
| Familial Mediterranean Fever. | Adam MP | - | 2016 | PMID: 20301405 |
| Defect of suppression of inflammasome-independent interleukin-8 secretion from SW982 synovial sarcoma cells by familial Mediterranean fever-derived pyrin mutations. | Sugiyama R | Molecular biology reports | 2014 | PMID: 24318677 |
| Prevalence of known mutations and a novel missense mutation (M694K) in the MEFV gene in a population from the Eastern Anatolia Region of Turkey. | Yesilada E | Gene | 2012 | PMID: 23031807 |
| Homozygous M694V as a risk factor for amyloidosis in Turkish FMF patients. | Akpolat T | Gene | 2012 | PMID: 22037353 |
| Screening for the M694V mutation of the familial Mediterranean fever (FMF) gene in 604 French patients. | Bathelier C | Genetic counseling (Geneva, Switzerland) | 2010 | PMID: 21290976 |
| 1Novel MEFV transcripts in Familial Mediterranean fever patients and controls. | Medlej-Hashim M | BMC medical genetics | 2010 | PMID: 20534143 |
| Isolated recurrent pleuritis revealing familial mediterranean Fever in adulthood. | Lega JC | Respiration; international review of thoracic diseases | 2010 | PMID: 20051664 |
| A case of familial Mediterranean fever associated with compound heterozygosity for the pyrin variant L110P-E148Q/M680I in Japan. | Oshima K | Modern rheumatology | 2010 | PMID: 19967574 |
| Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels. | Feng J | PloS one | 2009 | PMID: 20041150 |
| MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever. | Bonyadi M | Clinical genetics | 2009 | PMID: 19863562 |
| Presentation of familial Mediterranean fever in a heterozygous MEFV mutation triggered by immunosuppressive therapy for myelodysplastic syndrome. | Sasaki K | International journal of hematology | 2009 | PMID: 19466506 |
| The fate of 12 recessive mutations in a single village. | Zlotogora J | Annals of human genetics | 2007 | PMID: 17331080 |
| Familial Mediterranean fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype-genotype correlation. | Mattit H | European journal of medical genetics | 2006 | PMID: 16627024 |
| Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. | Medlej-Hashim M | European journal of medical genetics | 2005 | PMID: 16378925 |
| The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. | Majeed HA | Seminars in arthritis and rheumatism | 2005 | PMID: 15942916 |
| A Japanese patient with familial Mediterranean fever associated with compound heterozygosity for pyrin variant E148Q/M694I. | Nakamura A | Internal medicine (Tokyo, Japan) | 2005 | PMID: 15805719 |
| E148Q/M694I mutation in 3 Japanese patients with familial Mediterranean fever. | Kotone-Miyahara Y | International journal of hematology | 2004 | PMID: 15168590 |
| Familial Mediterranean fever in 2 Japanese families. | Shinozaki K | The Journal of rheumatology | 2002 | PMID: 12064853 |
| The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. | Gershoni-Baruch R | European journal of human genetics : EJHG | 2002 | PMID: 11938447 |
| The genetic basis of autosomal dominant familial Mediterranean fever. | Booth DR | QJM : monthly journal of the Association of Physicians | 2000 | PMID: 10787449 |
| MEFV mutations in Turkish patients suffering from Familial Mediterranean Fever. | Akar N | Human mutation | 2000 | PMID: 10612841 |
| MEFV-Gene analysis in armenian patients with Familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications. | Cazeneuve C | American journal of human genetics | 1999 | PMID: 10364520 |
| Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. | Aksentijevich I | American journal of human genetics | 1999 | PMID: 10090880 |
| Pyrin/marenostrin mutations in familial Mediterranean fever. | Booth DR | QJM : monthly journal of the Association of Physicians | 1998 | PMID: 10024914 |
| Phenotype-genotype correlation in Jewish patients suffering from familial Mediterranean fever (FMF). | Dewalle M | European journal of human genetics : EJHG | 1998 | PMID: 9781020 |
| A candidate gene for familial Mediterranean fever. | French FMF Consortium | Nature genetics | 1997 | PMID: 9288094 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MEFV | - | - | - | - |
| https://infevers.umai-montpellier.fr/ | - | - | - | - |
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Text-mined citations for rs28940578 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 2024
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.