ClinVar Genomic variation as it relates to human health

Variant summary: The MEFV c.2282G>A variant affects a non-conserved nucleotide, resulting in amino acid change from Arg to His. 2/4 in-silico tools predict this variant to be deleterious. This variant was found in 28/121772 control chromosomes at a frequency of 0.0002299, which does not exceed maximal expected frequency of a pathogenic MEFV allele (0.0216506). In addition, this variant is considered pathogenic in the literature and has been identified in many FMF patients in homozygous and compound heterozygous state. Taken together, this variant was classified as pathogenic.

NM_000243.2(MEFV):c.2282G>A(R761H) is classified as 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 MEFV mutation status is uncertain. Sources cited for classification include the following: PMID 19863562, 16378925 and 9668175. Classification of NM_000243.2(MEFV):c.2282G>A(R761H) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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.

The p.Arg761His (NM_000243.2 c.2282G>A) variant in MEFV has been reported in over 20 heterozygous, 10 homozygous, and 50 compound heterozygous individuals with familial Mediterranean fever (FMF) (Bernot 1998 PMID: 9668175, Ece 2015 PMID: 24071932, Salehzadeh 2015 PMID: 25648235, Beheshtian 2016 PMID: 27659338). It has also been reported in ClinVar (Variation ID# 2549), as pathogenic. This variant has been identified in 0.2% (38/18870) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104895097). This frequency is low enough to be consistent with a recessive carrier frequency. In summary, the p.Arg761His variant meets criteria to be classified as pathogenic for FMF in an autosomal recessive manner based upon its occurrence in affected individuals. ACMG/AMP criteria applied: PM3_VStrong, PP2.

The c.2282G>A (p.R761H) alteration is located in exon 10 (coding exon 10) of the MEFV gene. This alteration results from a G to A substitution at nucleotide position 2282, causing the arginine (R) at amino acid position 761 to be replaced by a histidine (H)._x000D_ _x000D_ Based on the available evidence, the clinical significance of the MEFV c.2282G>A (p.R761H) alteration is uncertain for autosomal dominant familial Mediterranean fever (FMF); however, this variant is likely pathogenic for autosomal recessive FMF. Based on data from gnomAD, the A allele has an overall frequency of 0.02% (58/282,828) total alleles studied. The highest observed frequency was 0.19% (38/19,954) of East Asian alleles. This alteration has been reported homozygous or compound heterozygous with a second mutation in MEFV in multiple patients with autosomal recessive familial Mediterranean fever (FMF) (Bernot, 1998; Bonyadi, 2009; Ece, 2014; Salehzadeh, 2015). It has also been reported heterozygous in patients with a milder form of FMF (Moradian, 2010; Procopio, 2018). Of these cases, 25% were associated with fever (Procopio, 2018) This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Across a selection of available literature, the MEFV c.2282G>A (p.Arg761His) missense variant has been identified in 82 patients with familial Mediterranean fever, including in a homozygous state in seven patients, in a compound heterozygous state in 50 patients, and in a heterozygous state in 25 patients (Bernot A et al. 1998; Bonyadi M et al. 2009; Ece A et al. 2013; Neocleous et al. 2014; Salehzadeh et al. 2015). Moradian et al. (2014) found the p.Arg761His variant at a frequency of 3.46% in a population of 16,000 Armenian familial Mediterranean fever patients, while the frequency of the variant in the control group was 0.20%. The p.Arg761His variant was absent from 99 controls and is reported at a frequency of 0.00231 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg761His 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.

The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene.

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18496034, 22580583, 23844200, 22953644, 27980538, 28486679, 10090880, 9668175, 23588594, 22975760, 23907647, 18000697, 19934083, 24141617, 10364520, 25727825, 19479870, 18328141, 25232290, 25202401, 24592325, 19863562, 27621632, 25449140, 26351556, 26543317, 30609409, 29543225, 30476289, 31376265, 30783801, 28828621, 34426522, 31589614, 29080837, 27659338, 25648235, 25703702, 25615955, 25393764, 19302049)

The MEFV c.2282G>A; p.Arg761His variant (rs104895097) has been described in the homozygous, heterozygous, and compound heterozygous states in individuals affected with familial Mediterranean fever (FMF; Berdeli 2011, Bernot 1998, Moradian 2014, Neocleous 2015, Ong 2013). It is reported as pathogenic in ClinVar (Variation ID: 2549) and observed in the general population at an overall frequency of 0.02% (58/282,828 alleles) in the Genome Aggregation Database. The arginine at codon 761 is weakly conserved, computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.352). Additionally, another variant at this codon (c.2281C>A; p.Arg761His) has been described in multiple individuals affected with FMF and is considered pathogenic (Ozalkaya 2011). Based on available information, the p.Arg761His variant is considered pathogenic. REFERENCES Berdeli A et al. Comprehensive analysis of a large-scale screen for MEFV gene mutations: do they truly provide a "heterozygote advantage" in Turkey? Genet Test Mol Biomarkers. 2011 Jul-Aug;15(7-8):475-82. 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. Moradian M et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 2014 Mar;16(3):258-63. Neocleous V et al. Familial Mediterranean fever associated with MEFV mutations in a large cohort of Cypriot patients. Ann Hum Genet. 2015 Jan;79(1):20-7. Ong F et al. The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA. Clin Genet. 2013 Jul;84(1):55-9. Ozalkaya E et al. Familial Mediterranean fever gene mutation frequencies and genotype-phenotype correlations in the Aegean region of Turkey. Rheumatol Int. 2011 Jun;31(6):779-84.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 761 of the MEFV protein (p.Arg761His). This variant is present in population databases (rs104895097, gnomAD 0.2%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 9668175, 17566872, 21413889, 23031807, 23038988, 23907647, 25393764, 26351556, 27980538). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2549). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Pathogenic.

MEFV: PM3:Very Strong, PM2:Supporting, PS3:Supporting

The MEFV c.2282G>A variant is predicted to result in the amino acid substitution p.Arg761His. This variant has previously been reported in the compound heterozygous state in individuals who presented with familial Mediterranean fever (FMF; see Bernot et al. 1998. PubMed ID: 9668175; Moradian et al. 2014. PubMed ID: 23907647; http://fmf.igh.cnrs.fr/ISSAID/infevers/). This variant is reported in 0.19% of alleles in individuals of East Asian descent in gnomAD and is classified as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/2549/). We interpret this variant to be pathogenic.