ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.442G>C (rs3743930)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000513398 SCV000227072 pathogenic not provided 2017-09-27 criteria provided, single submitter clinical testing
GeneDx RCV000513398 SCV000279030 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing The E148Q variant in exon 2 of the MEFV gene has been described in individuals from many different ethnic backgrounds, and has been identified on 24% of FMF chromosomes that do not have a pathogenic variant in the most commonly mutated exon 10 (Bernot et al., 1998; Masters et al., 2009). However, a recent meta-analysis reported that the E148Q variant was present in 58/824 FMF alleles (7.0%) and in 163/2802 control alleles (5.8%) (Marek-Yagel et al., 2009). Therefore, it is currently unclear if E148Q is a pathogenic variant with low penetrance and mild symptoms, or a benign variant due to its similar frequency among patients and controls.
PreventionGenetics,PreventionGenetics RCV000218652 SCV000303125 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002651 SCV000396780 likely benign Familial Mediterranean fever 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283338 SCV000604166 benign none provided 2020-08-27 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513398 SCV000608745 likely benign not provided 2017-04-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000218652 SCV000696072 uncertain significance not specified 2020-12-18 criteria provided, single submitter clinical testing Variant summary: MEFV c.442G>C (p.Glu148Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. While the pathogenicity of this variant remains controversial, there have been several studies of symptomatic patients in certain ethnic backgrounds. The variant allele was found at a frequency of 0.072 in 236468 control chromosomes (gnomAD and publications), including 2070 homozygotes, well above the ACMG guideline of 5% threshold for an allele, strongly suggesting this variant lies in the benign spectrum. Particularly, this variant was found at a frequency of 28% in Asian population (East and South Asian) in gnomAD including 2013 homozygous occurrences. The population-based studies, therefore, strongly supports the hypothesis that E148Q is a benign polymorphism and not a disease-causing mutation. But there are numerous studies that associate the p.E148Q variant with FMF in certain ethnic backgrounds and report that it is a low penetrance pathogenic variant in specific genetic backgrounds (Ben-Chetrit_2000, Tchernitchko_2003). Apart from Asian population, it is relatively rare in other control populations: frequencies are in the range of 2% in European and African cohorts of gnomAD. This variant is predominant in Ashkenazi and Iraqi Jews, Armenians, and Turks, and has been associated with a generally mild form of FMF (Aksentijevich_1999,Tchernitchko_2003). This variant is regarded as one of the five mutations (p.Met680Ile (G>C), p.Met694Val, p.Met694Ile (G>T), and p.Val726Ala on exon 10, and p.Glu148Gln) that explain 85% of FMF cases in Middle East. In multiple unrelated patients, this variant also has been reported to be in cis with a pathogenic variant including V726A, M694V, M694I (Bernot_1998, Topaloglu_2005, Aksentijevich_1999). A recent publication reported this variant in association with increased levels of Amyloid A in Egyptian patients (Mansour_2019). It is worth noting that the majority of publications citing this variant in FMF cohorts do not perform comprehensive MEFV analysis, thus pathogenic variants may have been missed, which would explain the similar observed allele frequencies in patients and unaffected controls. Recently, the SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) initiative has developed evidence-based recommendations for genetic diagnosis of FMF and according to these recommendations, the E148Q variant is common, of unknown pathogenic significance and, as the only MEFV variant, does not support the genetic diagnosis of FMF. One publication reports this variant causes less suppression of IL-8 secretion in cells compared to WT (Sugiyama_2014) which may reflect the activity in FMF arthritis. Eleven clinical diagnostic laboratories and one database (GeneReviews) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation reporting conflicting assessments ranging from likely benign/benign (n=6), VUS (n=5) and pathogenic (n=1). Several submitters have cited overlapping evidence utilized in the context of this evaluation. Taken together, the p.Glu148Gln variant could be very low penetrant pathogenic variant in certain genetic as well as ethnic backgrounds; however additional information is needed to fully assess its clinical significance. Based on the evidence outlined above, the variant retained its classification as uncertain significance.
Invitae RCV000002651 SCV000753982 likely benign Familial Mediterranean fever 2020-11-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 148 of the MEFV protein (p.Glu148Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs3743930, gnomAD 29%) including 2140 homozygotes. This variant has been reported in the literature in many individuals affected with familial mediterranean fever (FMF) as homozygous, compound heterozygous in the presence of a second pathogenic variant, heterozygous without an identified second pathogenic variant, and as part of complex genotypes with more than two identified pathogenic variants (PMID: 11938447, 15717684, 15458961, 18662100, 19820229, 24797171, 26215181). Many studies of this variant have small sample sizes and/or only examine selected exons or variants in the MEFV gene. The p.Glu148Gln variant has also been reported in many asymptomatic individuals (PMID: 12955725, 19820229, 23907647), including those retrospectively identified from non-MEFV carrier screening programs (PMID: 19929404, 10090880). Recent studies comparing the frequency of p.Glu148Gln in cases and controls or unaffected relatives have not found a significant difference in these two groups, although none of these studies have included greater than 1,000 cases and 1,000 controls (PMID: 10737995, 19820229, 23907647). A population level analysis of MEFV has suggested that the frequency of calculated disease prevalence only matches observed prevalence of disease if the p.Glu148Gln variant is excluded or considered a very low penetrant allele (PMID: 23844200). Several segregation analyses have shown partial or lack of segregation in affected families (PMID: 10737995, 12955725, 16439437). ClinVar contains an entry for this variant (Variation ID: 2542). In one experimental study this variant had a decreased effect in suppressing IL-8 secretion compared to wild-type in vitro and in blood mononuclear cells from affected individuals compared to healthy controls (PMID: 24318677). The clinical significance of these results is unknown. An ex vivo colchicine functional assay showed that the functional response in patients with this variant was similar to healthy controls and these patients did not respond to treatment with colchicine (PMID: 32312770). In summary, while this variant has been reported in the literature in many individuals affected with FMF and may have an effect on protein function, it is observed in a high frequency in population databases and in healthy controls and does not segregate with disease in several families. Based on the available evidence it has been classified as likely benign.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000761446 SCV000891531 uncertain significance Familial mediterranean fever, autosomal dominant 2017-12-30 criteria provided, single submitter curation
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768024 SCV000898827 uncertain significance Familial Mediterranean fever; Familial mediterranean fever, autosomal dominant 2020-03-20 criteria provided, single submitter clinical testing MEFV NM_000243.2 exon 2 p.Glu148Gln (c.442G>C): This variant has been well reported in the literature and identified in several individuals with Familial Mediteranean Fever (FMF) as homozygous, compound heterozygous or compound heterozygous as part of a complex allele containing this variant and p.Val726Ala, with the latter found in trans with a different pathogenic variant (Bernot 1998 PMID:9668175, Kogan 2001 PMID:11484206, Gershoni-Baruch 2002 PMID:11938447). However, several publications claim that this variant is a benign polymorphism, suggesting equal incidence of this variant in affected individuals and control populations (Ben-Chetrit 2000 PMID:10737995, Tchernitchko 2003 PMID:12955725, Zaks 2003 PMID:12929299, Marek-Yagel 2009 PMID:19820229). A GeneReviews entry for FMF also notes the discrepant interpretation of this variant (Shohat 2016 PMID:20301405). This variant is present in 3% (5347/18284) of East Asian alleles, including 779 homozygotes, in the Genome Aggregation Database ( This frequency is present at similar percentages among alleles of other ethnicities as well. This variant is present in ClinVar (Variation ID:2542). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000002651 SCV000930490 likely benign Familial Mediterranean fever 2019-04-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000513398 SCV001134282 uncertain significance not provided 2019-02-08 criteria provided, single submitter clinical testing
Mendelics RCV000002651 SCV001139889 benign Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000761446 SCV001428927 pathogenic Familial mediterranean fever, autosomal dominant 2017-12-13 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center,Al Jalila Childrens Speciality Hospital RCV000768024 SCV001448263 uncertain significance 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 RCV000513398 SCV001450089 pathogenic not provided 2014-06-26 criteria provided, single submitter clinical testing
OMIM RCV000002651 SCV000022809 uncertain significance Familial Mediterranean fever 2002-01-01 no assertion criteria provided literature only
GeneReviews RCV000002651 SCV000484959 uncertain significance Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000002651 SCV000606900 not provided Familial Mediterranean fever no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc. RCV000002651 SCV001462426 benign Familial Mediterranean fever 2020-05-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000513398 SCV001552621 uncertain significance not provided no assertion criteria provided clinical testing The MEFV p.Glu148Gln variant was identified in 112 of 2364 proband chromosomes (frequency: 0.047) from individuals or families with Familial Mediterranean fever (FMF) or hereditary recurrent fevers (HRFs) (Neocleous_2015_PMID:25393764; Solak_2008_PMID:18662100; Tchernitchko_2003_PMID:12955725). However Tchernitchko et al. (2003) identified the variant at a similar frequency in Sephardic Jewish FMF patients as well as their unaffected relatives (Tchernitchko_2003_PMID:12955725). Further, one study found that the E148Q vairant segregated with disease in only 3 of 18 families with FMF (Tchernitchko_2006_PMID:16439437). Milder FMF has been reported in patients homozygous for E148Q compared to other MEFV variants (Topaloglu_2018_PMID:27457448). The variant was identified in dbSNP (ID: rs3743930), ClinVar (classified as pathogenic once, a VUS 8 times, likely benign 3 times and benign once) and LOVD 3.0 (classified as a VUS). The variant was also identified in control databases in 17464 of 265578 chromosomes (2140 homozygous) at a frequency of 0.065758 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 5580 of 19142 chromosomes (freq: 0.2915), South Asian in 8603 of 30266 chromosomes (freq: 0.2842), Ashkenazi Jewish in 552 of 9938 chromosomes (freq: 0.05554), Other in 291 of 6920 chromosomes (freq: 0.04205), African in 328 of 22856 chromosomes (freq: 0.01435), European (non-Finnish) in 1619 of 119630 chromosomes (freq: 0.01353), Latino in 453 of 34580 chromosomes (freq: 0.0131), and European (Finnish) in 38 of 22246 chromosomes (freq: 0.001708). The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu148 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The structural effect of the E148Q variant was predicted to be low by a quantum chemistry-based model (Naimushin_2011_PMID:21598804). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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