ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.1958G>A (p.Arg653His)

gnomAD frequency: 0.00007  dbSNP: rs104895085
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000255083 SCV000224798 pathogenic not provided 2014-10-14 criteria provided, single submitter clinical testing
GeneDx RCV000255083 SCV000321877 pathogenic not provided 2016-05-02 criteria provided, single submitter clinical testing The R653H pathogenic variant in the MEFV that has been previously reported in association with Familial Mediterranean Fever (FMF) (Schaner et al., 2001; Timmann et al., 2001; Booty et al., 2009; Lazarin et al., 2013). It has also been observed in patients with juvenile idiopathic arthritis (Comak et al., 2013). The R653 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R653H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, a missense variant in a nearby residue (E656A) has been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002662 SCV000696058 pathogenic Familial Mediterranean fever 2017-02-23 criteria provided, single submitter clinical testing Variant summary: The MEFV c.1958G>A (p.Arg653His) variant located in the SPRY domain (via InterPro) involves the alteration of a non-conserved nucleotide, which 2/3 in silico tools (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a benign outcome for this variant, although these predictions have yet to be functionally assessed. This variant was found in 6/121204 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). Multiple publications have cited the variant in affected individuals in whom a second mutation not identified. Of note, this variant was reported in one affected individual who met the Tel-Hashomer criteria for a diagnosis of MEFV as a compound heterozygote along with p.M694V. The unaffected mother and brother were carriers for the variant of interest. In addition, Booty_2009 reports a clinically diagnosed FMF affected sib-pair that each carry only the variant of interest following a comprehensive search for a second mutation in the MEFV gene. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, although no in-vitro or in-vivo functional studies supporting a damaging outcome for this variant have been reported, the ascertained evidence has been weighted to classify this variant as Pathogenic.
Mendelics RCV000002662 SCV001139836 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000002662 SCV001415945 likely pathogenic Familial Mediterranean fever 2024-01-27 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 653 of the MEFV protein (p.Arg653His). This variant is present in population databases (rs104895085, gnomAD 0.01%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 11470495, 16378925, 19479870, 21413889, 24469716, 29159471, 31989427; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2553). 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. 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.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000255083 SCV001449978 likely pathogenic not provided 2019-12-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000255083 SCV002048973 likely pathogenic not provided 2021-02-18 criteria provided, single submitter clinical testing The MEFV c.1958G>A; p.Arg653His variant (rs104895085) has been described in the heterozygous state in several individuals with a clinical diagnosis of familial Mediterranean fever and at least once in the compound heterozygous state in an individual with an additional pathogenic variant (Berdeli 2011, Botty 2009, Comak 2013, Jeske 2013, Oztuzcu 2014, Schaner 2001, Shinar 2007, Timmann 2001). The variant is reported in the ClinVar database (Variation ID: 2553) and is listed in the general population with an overall allele frequency of 0.0035% (10/282,580 alleles) in the Genome Aggregation Database. The arginine at codon 653 occurs in the SPRY domain, is weakly conserved, computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.337). However, most pathogenic MEFV variants occur in the SPRY domain (Manukyan 2016). Based on available information, this variant is classified as likely 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. Booty MG et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 2009 Jun;60(6):1851-61. Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 Aug;172(8):1061-7. Jeske M et al. Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study. Klin Padiatr. 2013 Nov;225(6):325-30 Manukyan G and Aminov R Update on Pyrin Functions and Mechanisms of Familial Mediterranean Fever. Front. Microbiol. 2016 7:456. 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. Schaner P et al. Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states. Nat Genet. 2001 Mar;27(3):318-21. Shinar Y et al. Unique spectrum of MEFV mutations in Iranian Jewish FMF patients--clinical and demographic significance. Rheumatology (Oxford). 2007 Nov;46(11):1718-22. Timmann C et al. Two novel mutations R653H and E230K in the Mediterranean fever gene associated with disease. Mutat Res. 2001 Aug 8;479(1-2):235-9.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center RCV000002662 SCV003930290 pathogenic Familial Mediterranean fever 2023-06-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV003466788 SCV004194406 likely pathogenic Familial Mediterranean fever, autosomal dominant 2023-10-24 criteria provided, single submitter clinical testing
OMIM RCV000002662 SCV000022820 pathogenic Familial Mediterranean fever 2001-03-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000002662 SCV000115818 not provided Familial Mediterranean fever no assertion provided not provided
GeneReviews RCV000002662 SCV000484964 not provided Familial Mediterranean fever no assertion provided literature only
Counsyl RCV000002662 SCV001132429 likely pathogenic Familial Mediterranean fever 2019-03-15 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.