ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.2282G>A (p.Arg761His) (rs104895097)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000217233 SCV000884105 pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing The MEFV c.2282G>A; p.Arg761His variant (rs104895097) has been described in the homozygous, heterozygous, and compound heterozygous states in association 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% (56/277198 alleles) in the Genome Aggregation Database. The arginine at codon 761 is weakly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated; however, functional studies have not been performed to confirm the effect of this variant on protein structure and/or function. Another variant at this codon (c.2281C>A; p.Arg761His) has been described in multiple individuals 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. "
Counsyl RCV000002658 SCV000678043 pathogenic Familial Mediterranean fever 2017-06-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000217233 SCV000331538 pathogenic not provided 2016-03-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763379 SCV000894078 likely pathogenic Familial Mediterranean fever; Familial mediterranean fever, autosomal dominant 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000217233 SCV000279064 pathogenic not provided 2017-09-08 criteria provided, single submitter clinical testing The R761H variant in the MEFV gene has been observed in the homozygous state and with other pathogenic variants in affected individuals from multiple ethnic backgrounds, and accounts for approximately 3.5% of identifiable MEFV variants (Bernot et al., 1998; Aksentijevich et al., 1999; Bonyadi et al., 2009; Salehzadeh et al. 2015; Uluca et al., 2015). The variant is observed in 20/8650 (0.231%) alleles from individuals of East Asian background in the ExAC dataset (Lek et al.). R761H is a conservative amino acid substitution which occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or this variant is damaging to the protein structure/function. Additionally, a missense variant at the same codon (R761S) has been reported in patients with FMF (Ozalkaya et al., 2011). Therefore, we interpret R761H as a pathogenic variant.
GeneReviews RCV000002658 SCV000484974 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000002658 SCV000746540 pathogenic Familial Mediterranean fever 2017-12-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002658 SCV000396759 pathogenic Familial Mediterranean fever 2017-04-27 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America RCV000002658 SCV000696064 pathogenic Familial Mediterranean fever 2016-04-28 criteria provided, single submitter clinical testing 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.
Invitae RCV000002658 SCV000629040 likely pathogenic Familial Mediterranean fever 2019-01-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 761 of the MEFV protein (p.Arg761His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs104895097, ExAC 0.2%). This variant is a common cause of familial Mediterranean fever in Turkey, Cyprus, Lebanon, and Iran, although it has also been reported in other populations (PMID: 9668175, 17566872, 21413889, 23907647, 23031807, 23038988, 25393764, 26351556, 27980538). This variant has been reported in homozygous, heterozygous and compound heterozygous statuses in affected individuals (PMID: 21413889, 25393764, 25615955). 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000002658 SCV000711425 pathogenic Familial Mediterranean fever 2017-09-06 criteria provided, single submitter clinical testing The p.Arg761His (NM_000243.2 c.2282G>A) variant in MEFV has been reported in ove r 20 heterozygous, 10 homozygous, and 50 compound heterozygous individuals with familial Mediterranean fever (FMF) (Bernot 1998, Ece 2015, Salehzadeh 2015, Behe shtian 2016). It has also been reported in ClinVar (Variation ID#2549), as patho genic. This variant has been identified in 0.2% (38/18870) of East Asian chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs104895097). This frequency is low enough to be consistent with a rece ssive carrier frequency. In summary, the p.Arg761His variant meets criteria to b e classified as pathogenic for FMF in an autosomal recessive manner based upon i ts occurrence in affected individuals.
OMIM RCV000002658 SCV000022816 pathogenic Familial Mediterranean fever 1998-08-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000002658 SCV000115856 not provided Familial Mediterranean fever no assertion provided not provided

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