ClinVar Miner

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

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 RCV000999738 SCV000604174 pathogenic not specified 2018-11-08 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 (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: 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 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing
Invitae RCV000002657 SCV000629039 pathogenic Familial Mediterranean fever 2019-01-09 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
OMIM RCV000002657 SCV000022815 pathogenic Familial Mediterranean fever 1998-08-01 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000002657 SCV000052845 pathogenic Familial Mediterranean fever 2015-07-02 no assertion criteria provided clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000002657 SCV000115851 not provided Familial Mediterranean fever no assertion provided not provided
Counsyl RCV000002657 SCV000220753 likely pathogenic Familial Mediterranean fever 2019-04-03 no assertion criteria provided clinical testing
GeneReviews RCV000002657 SCV000484973 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only

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