Submissions for variant NM_000243.3(MEFV):c.442G>C (p.Glu148Gln)

gnomAD frequency: 0.02112  dbSNP: rs3743930

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513398	SCV000279030	likely benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Illumina Laboratory Services, 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	RCV000513398	SCV000604166	benign	not provided	2023-11-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics 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	2024-07-30	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. The variant allele was found at a frequency of 0.072 in 236468 control chromosomes in the gnomAD database, including 2070 homozygotes, well above the ACMG guideline of 5% threshold for an allele, strongly suggesting this variant lies in the benign spectrum. Notably, this variant was found at a frequency of 28% in the Asian population (East and South Asian) in gnomAD, including 2013 homozygous occurrences. These population-based frequencies therefore, strongly support 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 the 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 several mutations (p.Glu148Gln, p.Met680Ile, p.Met694Val, p.Met694Ile, and p.Val726Ala on exon 10) that explain 85% of FMF cases in the Middle East. In multiple unrelated patients, this variant also has been reported to be in cis with a pathogenic variant including V726A, M694V, M694I (e.g. Bernot_1998, Topaloglu_2005, Aksentijevich_1999, Reygaerts_2024). A recent publication has also 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. Data obtained from a recent study of the largest paediatric FMF cohort in Israel, suggest that a single heterozygous E148Q variant is highly unlikely to aggravate the FMF phenotype. Patients with the variant exhibited a milder phenotype, since most had questionable FMF diagnosis and were asymptomatic during prolonged follow-up off colchicine treatment (Tirosh_2021). On the other hand, another recent study using controls and patients of North African Jewish descent, determined that the penetrance of p.[Met694Val];[Glu148Gln] is more than 17 times higher than p.[Met694Val];[=], indicating an active role for p.Glu148Gln when combined with p.Met694Val (Eyal_2020). 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. Another publication reported IL-1 beta and IL-18 ratios of E148Q similar to controls in an ex vivo colchicine assay, while colchicine was not beneficial in patients with this variant (Van Gorp_2020). The following publications have been ascertained in the context of this evaluation (PMID: 10090880, 10737995, 9668175, 25866490, 32741030, 33497256, 11938447, 35780723, 26131005, 25261100, 25073670, 30915208, 20534143, 21598804, 25393764, 29080837, 24433404, 35490273, 15024140, 18097735, 24318677, 12955725, 33560333, 15458961, 27457448, 11464238, 29599418, 32312770, 29314707, 37481715). ClinVar contains an entry for this variant (Variation ID: 2542). In 2018, the experts international study group for systemic autoinflammatory diseases (INSAID) reported a validated classification of uncertain significance for the variant (Van Gijn_2018). Taken together, the p.Glu148Gln variant could be a 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002651	SCV000753982	likely benign	Familial Mediterranean fever	2024-02-01	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, Sultan Qaboos University	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 (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.
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
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
Institute of Human Genetics, University of Leipzig Medical Center	RCV000002651	SCV002072564	uncertain significance	Familial Mediterranean fever	2022-01-24	criteria provided, single submitter	clinical testing	Variant identified together with variant Met694Val (phase unknown) in individual with clinical FMF phenotype
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251861	SCV002523073	uncertain significance	See cases	2022-03-30	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM3, BS2
Department of Human Genetics, Hannover Medical School	RCV000761446	SCV002525495	uncertain significance	Familial Mediterranean fever, autosomal dominant	2022-06-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262542	SCV002543456	uncertain significance	Autoinflammatory syndrome	2022-05-03	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000002651	SCV002579058	uncertain significance	Familial Mediterranean fever	2022-04-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326658	SCV002628289	benign	Inborn genetic diseases	2016-07-12	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224086	SCV003920210	benign	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2022-10-13	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000002651	SCV004805289	uncertain significance	Familial Mediterranean fever	2024-03-25	criteria provided, single submitter	research
Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	RCV000513398	SCV005328432	uncertain significance	not provided	2023-08-18	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000002651	SCV005329332	uncertain significance	Familial Mediterranean fever	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.442G>C (p.Glu148Gln) in MEFV gene has been reported previously in homozygous, compound heterozygous and heterozygous state in individuals affected with familial mediterranean fever (Gershoni-Baruch et al. 2002; Tirosh et al. 2021). Experimental evidence shows conflicting evidence of pathogenicity for this variant. One study showed a decreased effect in suppressing IL-8 secretion for this variant compared to wild-type in vitro and in blood mononuclear cells from affected individuals compared to healthy controls (Sugiyama et al. 2014); whereas, another study using a colchicine functional assay showed that the functional response for this variant in affected individuals was similar to healthy controls (Van Gorp et al. 2020). The p.Glu148Gln variant is present with an allele frequency of 7.1% (16654 heterozygotes; 2070 homozygotes) on gnomAD exomes database. This variant has been submitted to the ClinVar database Benign / Likely Benign / Uncertain Significance / Pathogenic. Computational evidence (SIFT - damaging; Polyphen - probably damaging; MutationTaster - polymorphism) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Glu148Gln in MEFV is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 148 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. This variant is one of the most common variant in MEFV gene and is present in significantly high number of healthy control population, with single heterozygous variant not reported to be associated significantly with familiar mediterranean fever in children (Van Gorp et al 2020). For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). In the absence of another reportable variant in the MEFV gene, the molecular diagnosis is not confirmed.
OMIM	RCV000002651	SCV000022809	uncertain significance	Familial Mediterranean fever	2002-01-01	no assertion criteria provided	literature only
Eurofins Ntd Llc (ga)	RCV000513398	SCV000227072	pathogenic	not provided	2017-09-27	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528067	SCV000303125	likely benign	MEFV-related disorder	2022-04-06	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
GeneReviews	RCV000002651	SCV000484959	not provided	Familial Mediterranean fever		no assertion 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000513398	SCV001450089	pathogenic	not provided	2014-06-26	flagged submission	clinical testing
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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000513398	SCV001928855	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000513398	SCV001952187	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000513398	SCV001963475	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513398	SCV001974762	uncertain significance	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000761446	SCV004041695	uncertain significance	Familial Mediterranean fever, autosomal dominant	2023-10-09	no assertion criteria provided	clinical testing