ClinVar Genomic variation as it relates to human health

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.

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 267 of the MEFV protein (p.Thr267Ile). This variant is present in population databases (rs104895081, gnomAD 0.03%). This missense change has been observed in individual(s) with familial Mediterranean fever and/or juvenile idiopathic arthritis or other autoinflammatory conditions (PMID: 9668175, 10737992, 16378925, 17489852, 20485448, 21413889, 23505238, 23588594, 24469716, 26003477). 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, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MEFV function (PMID: 33733382). 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.

Observed with a pathogenic variant on the same allele (in cis) in an individual with familial Mediterranean fever in published literature (Oztuzcu et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23505238, 20485448, 10737992, 25703702, 29178647, 28631068, 29314707, 29599418, 23588594, 16378925, 17384215, 11175300, 9668175, 26247045, 22975760, 29260407, 27457448, 28386255, 28624931, 27051312, 29735907, 29200027, 30488432, 20721559, 20645115, 15951859, 26003477, 34426522, 33733382, 36223753, 17489852, 24469716, 11781702)

Variant summary: 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 experts international study group for systemic autoinflammatory diseases (INSAID) decided a consensus classification of likely pathogenic for this variant (Van Gijn_2018). One experimental study reported no substantial increase in spontaneous cell death and TcdA/UCN-01-induced cell death enhancement due to the variant in transfected cells (Honda_2021). ClinVar contains an entry for this variant (Variation ID: 2544). 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.

The MEFV c.800C>T variant is predicted to result in the amino acid substitution p.Thr267Ile. This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD. It been reported in the homozygous state in an individual with familial Mediterranean fever (FMF) (Giaglis et al. 2007. PubMed ID: 17489852) and in the presence of a second MEFV variant; however, phase was not reported (Moradian et al. 2010. PubMed ID: 20485448; Oztuzcu et al. 2014. PubMed ID: 24469716). This variant was also reported in an individual with FMF and two other established pathogenic MEFV variants; however, the phase of this complex allele was not reported (Cornelius and Duno 2011. PubMed ID: 20721559). The c.800C>T (p.Thr267Ile) variant and another MEFV variant were reported in an individual with oligoarthritis; however, phase of the variants was not reported (Comak et al. 2013. PubMed ID: 23588594). This variant has been reported in the heterozygous state in individuals with FMF in which a second MEFV variant was not found or additional information on other variants was not provided (NAJ: 21-31, Bernot et al. 1998. PubMed ID: 9668175; Medlej-Hashim et al. 2005. PubMed ID: 16378925; Ceylan et al. 2012. PubMed ID: 22614345; Oztuzcu et al. 2014. PubMed ID: 24469716; Balta et al. 2020. PubMed ID: 31989427). Of note, FMF symptoms in patients with a single heterozygous MEFV variant could be due to an undetected second variant present in the gene or some patients with a single heterozygous variant could be mildly affected (Moradian et al. 2010. PubMed ID: 20485448). An in vitro functional study of monocytes expressing MEFV variants utilized flow cytometry to evaluate the impact the variants had on cell death showed that the p.Thr267Ile variant did not alter cell death rates and results were similar to that of wild type MEFV (Honda et al. 2021. PubMed ID: 33733382). Previous classifications of this variant determined it was causative (Shinar et al. 2012. PubMed ID: 22661645; Van Gijn et al. 2018. PubMed ID: 29599418; INFEVERS database); however, more recent classifications suggest this variant is of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/2544/). PreventionGenetics classified this variant as ‘pathogenic’ in 2015 based on the literature available at the time; however, based on current evidence the classification of this variant has shifted and now the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Variant interpreted as Uncertain significance and reported on 09-24-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.