ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.2082G>A (rs28940578)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002648 SCV000052841 pathogenic Familial Mediterranean fever 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
GeneDx RCV000220431 SCV000279059 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing The M694I missense variant in the MEFV gene has been frequently reported in association with FMF (Majeed et al., 2005; Moradian et al., 2014). In a series of 90 patients of different ethnic groups, M694I accounted for more than 5% of the MEFV pathogenic variants identified (Aksentijevich et al., 1999). The M694I variant is observed in 17/34420 (0.05%) alleles from individuals of Latino background, in the ExAC dataset (Lek et al., 2016). This variant occurs at a position within the B30.2/SPRY domain in which many other variants are clustered, supporting the functional importance of this region of the protein (Masters et al., 2009; Stenson et al., 2014). Additionally, functional studies reveal that M694I alters the level of IL8 secretion in vitro (Sugiyama et al., 2014). We interpret M694I as a pathogenic variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000220431 SCV000280932 pathogenic not provided 2015-12-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999740 SCV000604182 pathogenic none provided 2020-08-19 criteria provided, single submitter clinical testing 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% (35/277224 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. 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.
Broad Institute Rare Disease Group, Broad Institute RCV000589706 SCV000693895 pathogenic Familial mediterranean fever, autosomal dominant 2017-06-25 criteria provided, single submitter research
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000220431 SCV000854900 pathogenic not provided 2017-10-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763380 SCV000894079 pathogenic Familial Mediterranean fever; Familial mediterranean fever, autosomal dominant 2018-10-31 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000763380 SCV000898824 pathogenic Familial Mediterranean fever; Familial mediterranean fever, autosomal dominant 2017-10-19 criteria provided, single submitter clinical testing 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.
Invitae RCV000002648 SCV000933995 pathogenic Familial Mediterranean fever 2019-12-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 694 of the MEFV protein (p.Met694Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs28940578, ExAC 0.06%). This variant has been observed as homozygous or in combination with other MEFV variants in individuals affected with familial Mediterranean fever (FMF) (PMID: 12064853, 15168590, 15805719, 20051664), and has been shown to segregate with FMF in several families (PMID: 10787449, 12064853). ClinVar contains an entry for this variant. ClinVar contains an entry for this variant (Variation ID: 2539). Experimental studies have shown that this missense change reduces the suppression of IL8 secretion in synovial cell cultures (PMID: 24318677). Variants that disrupt the p.Met694 amino acid residue in MEFV have been observed in affected individuals (PMID: 9781020, 10364520, 21290976, 22037353, 12064853). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000002648 SCV001139823 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000002648 SCV001193934 pathogenic Familial Mediterranean fever 2019-12-04 criteria provided, single submitter clinical testing 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000220431 SCV001245669 pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center,Al Jalila Childrens Speciality Hospital RCV000763380 SCV001448271 pathogenic Familial Mediterranean fever; Familial mediterranean fever, autosomal dominant 2020-10-04 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000220431 SCV001450267 pathogenic not provided 2014-12-18 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000220431 SCV001480074 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
OMIM RCV000002648 SCV000022806 pathogenic Familial Mediterranean fever 1997-09-01 no assertion criteria provided literature only
GeneReviews RCV000002648 SCV000484970 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Natera, Inc. RCV000002648 SCV001462097 pathogenic Familial Mediterranean fever 2020-09-16 no assertion criteria provided clinical testing

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