ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.800C>T (p.Thr267Ile) (rs104895081)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000991330 SCV000696080 uncertain significance not specified 2020-01-13 criteria provided, single submitter clinical testing MEFV c.800C>T (p.Thr267Ile) results in a non-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 0.00016 in 251456 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever, allowing no conclusion about variant significance. c.800C>T has been reported in the literature in homozygous, compound heterozygous, complex compound heterozygous and heterozygous genotypes, in studies of multiple individuals affected with and/or meeting established clinical criteria of Familial Mediterranean Fever (e.g. Bernot_1998, Ceylan_2012, Cornelius_2010, Dogan_2015, Giaglis_2007, Medlej-Hashim_2000, Moradian_2010). The extent of genotyping reported was variable ranging from targeted analysis to full sequencing of the MEFV gene. At-least one of these reports included a patient in whom two other bonafide pathogenic variants that are well reported as causative of FMF, namely p.Met694Val and p.Val726Ala were identified (Cornelius_2010). In 2012, a group of clinical and molecular experts reached a consensus to test for a total of 14 MEFV variants, including p.Thr267Ile which they described as ‘clearly pathogenic’ (Shinar_2012). In 2018, the expert’s international study group for systemic autoinflammatory diseases (INSAID) decided a consensus classification of ‘likely pathogenic’ for this variant (Van Gijn_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance using overlapping evidences utilized in the context of this evaluation. Our laboratory classified this variant as 'pathogenic' in 2016 weighting the expert panel opinion (Shinar_2012) and reports of its presence in patients with clinically or suspected diagnosis of FMF. However, the prevailing consensus for this variant when observed in a clinical diagnostic setting seems to have shifted to an uncertain significance. Based on the evidence outlined above, the variant was re-classified as a VUS-possibly pathogenic.
Invitae RCV000002653 SCV000753975 uncertain significance Familial Mediterranean fever 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 267 of the MEFV protein (p.Thr267Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs104895081, ExAC 0.04%). This variant has been reported in heterozygous, compound heterozygous, and homozygous individuals affected with familial Mediterranean fever (PMID: 9668175, 10737992, 21413889, 17489852, 26003477, 20485448, 24469716, 16378925) and in individuals affected with juvenile idiopathic arthritis or other autoinflammatory conditions (PMID: 23588594, 23505238). ClinVar contains an entry for this variant (Variation ID: 2544). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000002653 SCV001139873 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000996177 SCV001150755 likely pathogenic not provided 2019-01-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000991330 SCV001156580 pathogenic not specified 2019-03-25 criteria provided, single submitter clinical testing The MEFV c.800C>T; p.Thr267Ile variant (rs104895081) has been published in the literature in individuals with familial Mediterranean fever (FMF) or juvenile idiopathic arthritis, with or without another pathogenic variant (Bernot 1998, Ceylan 2012, Comak 2013, Dogan 2015, Giaglis 2007, Oztuzcu 2014). This variant is listed in the ClinVar database (Variation ID: 2544) and listed in the general population with an overall allele frequency of 0.015% (42/282848 alleles) in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. References: Bernot A et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. Ceylan GG et al. Frequency of alterations in the MEFV gene and clinical signs in familial Mediterranean fever in Central Anatolia, Turkey. Genet Mol Res. 2012 May 7;11(2):1185-94. Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 Aug;172(8):1061-7. Dogan H et al. Familial Mediterranean fever gene mutations in north-eastern part of Anatolia with special respect to rare mutations. Gene. 2015 Sep 1;568(2):170-5. Giaglis S et al. MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever. Clin Genet. 2007 May;71(5):458-67. Oztuzcu S et al. Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep. 2014;41(4):2601-7.
OMIM RCV000002653 SCV000022811 pathogenic Familial Mediterranean fever 1998-08-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000002653 SCV000115896 not provided Familial Mediterranean fever no assertion provided not provided
Counsyl RCV000002653 SCV001132247 uncertain significance Familial Mediterranean fever 2018-05-14 no assertion criteria provided clinical testing

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