ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.442G>C (p.Glu148Gln) (rs3743930)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000513398 SCV000604166 likely benign not provided 2017-05-09 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
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 2018-01-26 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 two 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 (http://gnomad.broadinstitute.org/rs3743930). 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.
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
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.
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.
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
Illumina Clinical Services Laboratory,Illumina RCV000002651 SCV000396780 likely benign Familial Mediterranean fever 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000002651 SCV000052848 uncertain significance Familial Mediterranean fever 2015-10-05 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000513398 SCV000696072 uncertain significance not provided 2016-12-12 criteria provided, single submitter clinical testing
Invitae RCV000002651 SCV000753982 uncertain significance Familial Mediterranean fever 2017-12-04 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, ExAC 32%). In addition, there are a large number of homozygotes reported for this variant (ExAC 1038 homozygotes). This variant has been reported in the literature in many individuals affected with familial mediterranean fever (FMF), meeting Tel Hashomer criteria (PMID: 9336425), 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 containing more than 2 identified pathogenic variants (PMID: 11938447, 15717684, 15458961, 18662100, 19820229, 24797171, 26215181). It is important to note that many studies with the p.E148Q variant contain small sample sizes and/or only examine selected exons or variants in the MEFV gene. The p.E148Q 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.E148Q in cases versus controls or unaffected relatives, have not found a significant difference in these 2 groups, although none of these studies have included greater than 1,000 cases and 1,000 controls (PMID: 10737995, 19820229, 23907647). In addition, a population level analysis of MEFV has suggested that the frequency of calculated disease prevalence only matches observed prevalence of disease if the p.E148Q variant is excluded or considered a very low penetrant allele (PMID: 23844200). ClinVar contains an entry for this variant (Variation ID: 2542). Several segregation analyses have shown partial or lack of segregation in affected families (PMID: 10737995, 12955725, 16439437). In PMID: 10737995, 4 parents of unrelated FMF patients were homozygous for p.E148Q and asymptomatic. In addition, 2 parents who carried the p.E148Q did not transmit this allele to their affected child. In PMID: 12955725, the frequency of unaffected relatives with p.E148Q or unaffected relatives with p.M694V/p.E148Q were similar to the frequencies in affected FMF family members. In a follow-up study looking at segregation analysis for p.E148Q (PMID: 16439437), this variant segregated with disease in only 3 of 18 families with this variant. Two families showed partial segregation or reduced penetrance with p.E148Q, and in 13 families, p.E148Q did not segregate with disease. In total only 26% of affected FMF individuals inherited the p.E148Q variant (PMID: 16439437). In one experimental study this sequence change was found to have 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). However the clinical significance of these results is unknown. In summary, this variant has been reported in the literature in many individuals affected with FMF and may have an effect on protein function. However, it has also been observed in many healthy controls, is found at high frequency in population databases, and did not segregate with disease in several families, which suggests that this variant may be a neutral polymorphism. At this time however, reduced penetrance cannot be excluded. In the absence of large case-control studies and additional functional data, this variant has been classified as a Variant of Uncertain Significance.
OMIM RCV000002651 SCV000022809 uncertain significance Familial Mediterranean fever 2002-01-01 no assertion criteria provided literature only
PreventionGenetics RCV000218652 SCV000303125 benign not specified criteria provided, single submitter clinical testing

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