Submissions for variant NM_000243.3(MEFV):c.2282G>A (p.Arg761His)

gnomAD frequency: 0.00010  dbSNP: rs104895097

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000217233	SCV000279064	pathogenic	not provided	2022-05-11	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000217233	SCV000331538	pathogenic	not provided	2016-03-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Invitae	RCV000002658	SCV000629040	pathogenic	Familial Mediterranean fever	2024-01-28	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Laboratory for Molecular Medicine, Mass General Brigham 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000002658	SCV000746540	pathogenic	Familial Mediterranean fever	2017-12-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000217233	SCV000884105	pathogenic	not provided	2023-11-01	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 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.
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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000217233	SCV001134281	likely pathogenic	not provided	2019-02-08	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000002658	SCV001139807	pathogenic	Familial Mediterranean fever	2023-03-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000002658	SCV001194137	pathogenic	Familial Mediterranean fever	2019-12-20	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000217233	SCV001245667	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	MEFV: PM3:Very Strong, PM2:Supporting, PS3:Supporting
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000217233	SCV001450238	pathogenic	not provided	2014-07-28	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000217233	SCV001480075	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000002658	SCV001653432	likely pathogenic	Familial Mediterranean fever	2021-05-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001536101	SCV001752813	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-06-30	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000217233	SCV002009392	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000217233	SCV002017263	pathogenic	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262548	SCV002543742	pathogenic	Autoinflammatory syndrome	2022-04-29	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000002658	SCV002581685	pathogenic	Familial Mediterranean fever	2022-08-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512683	SCV003564644	likely pathogenic	Inborn genetic diseases	2021-08-13	criteria provided, single submitter	clinical testing	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). 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.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000002658	SCV004045784	pathogenic	Familial Mediterranean fever	2023-09-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466787	SCV004194408	pathogenic	Familial Mediterranean fever, autosomal dominant	2023-10-23	criteria provided, single submitter	clinical testing
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
GeneReviews	RCV000002658	SCV000484974	not provided	Familial Mediterranean fever		no assertion provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000217233	SCV001929002	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000217233	SCV001959586	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000217233	SCV001975132	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000002658	SCV002093873	pathogenic	Familial Mediterranean fever	2020-01-29	no assertion criteria provided	clinical testing