ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.2230G>T (rs61732874)

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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 RCV000999738 SCV000052845 uncertain significance not specified 2020-08-18 criteria provided, single submitter clinical testing Variant summary: MEFV c.2230G>T (p.Ala744Ser) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 252830 control chromosomes, predominantly at a frequency of 0.013 within the confined population of Ashkenazi Jewish in the gnomAD database, including 2 homozygotes. A study conducted using data from the National Center for FMF in Israel, estimated the total frequency of FMF allele occurrence in ASJ population to be 1:161 (i.e. 0.0062) (Lidar_2010). The reported allele frequency of c.2230G>T in the ASJ population in the gnomAD database is 2-fold of the estimated total frequency of FMF allele occurrence in ASJ (0.013 vs. 0.0062), suggesting that the variant is a benign polymorphism. Furthermore, recent studies in Arabic individuals (a population not represented in the gnomAD database) report the variant as benign/likely benign based on a population frequency of >1% and its presence in the homozygous state in multiple individuals who lack the FMF phenotype (Abouelhoda_2016, John_2018, Alsubaie_2020). Further evidence in support of benign polymorphism comes from Alsubaie et al (2020) reporting absence of favorable response to 6 months of colchicine therapy in two heterozygous cases with a clinical picture resembling FMF. c.2230G>T has been reported in the literature in the heterozygous, compound heterozygous or homozygous state in multiple individuals reported with symptoms of Familial Mediterranean Fever (e.g. Bernot_1998, Aksentijevich_1999, Tchernitchko_2003, Sabbagh_2008, Akin_2010, Jarjour_2010, Ozdemir_2011, Ceylan_2012, Neocleous_2015, Salehzadeh_2015, Mattit_2016, Gumus_2018) but has also been reported in healthy controls (e.g. Aldea_2004, Simsek_2011, John_2018). A lot of the studies (especially earlier ones that had led to the classification of the variant as pathogenic by multiple clinical providers), utilized only a restricted panel of variants or limited sequencing for targeted testing of individuals, while a large number of studies do not specify usage of Tel Hashomer clinical criteria to confirm diagnosis of FMF. 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). Therefore, these reports do not allow unequivocal conclusions about association of the variant with Familial Mediterranean Fever. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fifteen ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. A majority (fourteen) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter cites the variant as uncertain significance. However, it is not clear whether any of the submitters considered the recent reports by Alsubaie_2020 and Van Gijn_2018) in the context of their evaluation. Based on recent evidence that became available as outlined above, the variant was re-classified as uncertain significance from a previous classification of pathogenic.
GeneDx RCV000213702 SCV000279063 pathogenic not provided 2018-09-17 criteria provided, single submitter clinical testing The A744S variant in the MEFV gene is a common pathogenic variant that has been reported previously in association with familial Mediterranean fever (FMF) in families of various ancestries (Aksentijevich, 1999; Bernot et al., 1998; Rodriguez-Flores et al., 2014). The A744S variant is observed in 129/10,152 (1.3%) alleles from individuals of Ashkenazi Jewish background and 486/277,194 (0.18%) total alleles in large population cohorts, and two individuals were reported to be homozygous (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Modeling studies of the pyrin protein indicate that the A744S variant may affect folding of the binding cavity or impair interaction with other molecules (Goulielmos et al., 2006). We interpret A744S as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000213702 SCV000331539 pathogenic not provided 2017-06-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002657 SCV000396760 pathogenic Familial Mediterranean fever 2017-04-27 criteria provided, single submitter clinical testing The MEFV c.2230G>T (p.Ala744Ser) missense variant is well described in the literature as a pathogenic variant for familial Mediterranean fever (FMF). The variant has been reported in at least 12 studies in which it is found in at least 141 patients with FMF, including one homozygote, 26 compound heterozygotes, and 114 heterozygotes, plus an additional 56 of 4624 patient alleles where zygosity information is not provided (Bernot et al. 1998; Aksentijevich et al. 1999; Tchernitchko et al. 2003; Caglayan et al. 2010; Medlej-Hashim et al. 2010; Ait-Idir et al. 2011; Kilim et al. 2011; Ozdemir et al. 2011; Belmahi et al. 2012; Yesilad et al. 2012; Habahbeh et al. 2015; Salehzadeh et al. 2015). Across these studies, the variant was also reported in seven out of 950 control alleles. The p.Ala744Ser variant is also reported at a frequency of 0.01869 in the Iberian Populations in Spain cohort in the 1000 Genomes Project. This allele frequency is high but is consistent with estimates of disease prevalence. Based on the collective evidence, the p.Ala744Ser variant is classified as pathogenic for familial Mediterranean fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283654 SCV000604174 pathogenic none provided 2020-01-10 criteria provided, single submitter clinical testing The MEFV c.2230G>T; p.Ala744Ser variant (rs61732874) is reported as a common pathogenic variant in the literature, and is present in multiple individuals affected with Familial Mediterranean Fever (Beheshtian 2016, Habahbeh 2015, Salehzadeh 2015, Touitou 2001). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 2548), and is found in the general population with an overall allele frequency of 0.18% (499/282,842 alleles, including 2 homozygotes) in the Genome Aggregation Database. Based on available information, the p.Ala744Ser variant is considered to be pathogenic. REFERENCES Beheshtian M et al. Prevalence of common MEFV mutations and carrier frequencies in a large cohort of Iranian populations. J Genet. 2016 Sep;95(3):667-74. Habahbeh LA et al. Genetic Profile of Patients with Familial Mediterranean Fever (FMF): Single Center Experience at King Hussein Medical Center (KHMC). Med Arch. 2015 Dec;69(6):417-20. Salehzadeh F et al. MEFV Gene Profile in Northwest of Iran, Twelve Common MEFV Gene Mutations Analysis in 216 Patients with Familial Mediterranean Fever. Iran J Med Sci. 2015 Jan;40(1):68-72. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001 9(7):473-83.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000213702 SCV000608743 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
Invitae RCV000002657 SCV000629039 pathogenic Familial Mediterranean fever 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 744 of the MEFV protein (p.Ala744Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs61732874, ExAC 0.2%). This is a known prevalent MEFV variant that has been reported as heterozygous, homozygous, or compound heterozygous in multiple individuals affected with MEFV-related diseases (PMID: 17566872, 25793047, 19934083). In addition, it has been found consistently enriched among individuals affected with familial Mediterranean fever (FMF) in several populations (PMID: 26843738, 23031807, 20177433, 19449169). ClinVar contains an entry for this variant (Variation ID: 2548). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a prevalent rare missense change that has been consistently reported in affected individuals. Therefore, it has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768020 SCV000898821 pathogenic Familial Mediterranean fever; Familial mediterranean fever, autosomal dominant 2017-11-28 criteria provided, single submitter clinical testing MEFV NM_000243.2 exon 10 p.Ala744Ser (c.2230G>T): This variant is a well reported pathogenic variant in the literature (including a GeneReviews entry) and has been identified in several individuals with Familial Mediterranean Fever (FMF) (Bernot 1998 PMID:9668175, Aksentijevich 1999 PMID:10090880, Caglayan 2010 PMID:19934083, Ait-Idir 2011 PMID:22019805, Salehzadeh 2015 PMID:25648235, Shohat 2016 PMID:20301405). This variant is present in 1% (129/10152) of Ashkenazi Jewish alleles in the Genome Aggregation Database ( Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:2548). In summary, despite the presence of conflicting data (i.e. high frequency in the population, non-conserved amino acid position), this is consistent with the expected disease prevalence and carrier status of this condition. Therefore this variant is classified as pathogenic.
Mendelics RCV000002657 SCV001139810 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000002657 SCV001193781 likely pathogenic Familial Mediterranean fever 2019-12-31 criteria provided, single submitter clinical testing NM_000243.2(MEFV):c.2230G>T(A744S) is classified as likely 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 mutation status is uncertain. Sources cited for classification include the following: PMID 28590056, 20008924, 27659338, 27884173, 22019805, 23716950, 15024744, 19863562, 22661645, 19786432, 19934083, 26843738, 23031807, 20177433 and 19449169. Classification of NM_000243.2(MEFV):c.2230G>T(A744S) is based on the following criteria: This variant 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000213702 SCV001447980 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center,Al Jalila Childrens Speciality Hospital RCV000768020 SCV001448268 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 RCV000213702 SCV001450225 likely pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000002657 SCV001737246 likely pathogenic Familial Mediterranean fever 2021-05-18 criteria provided, single submitter clinical testing
OMIM RCV000002657 SCV000022815 pathogenic Familial Mediterranean fever 1998-08-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000002657 SCV000115851 not provided Familial Mediterranean fever no assertion provided not provided
GeneReviews RCV000002657 SCV000484973 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Natera, Inc. RCV000002657 SCV001462092 pathogenic Familial Mediterranean fever 2020-09-16 no assertion criteria provided clinical testing

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