ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1958G>A (p.Arg653His) (rs104895085)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 uncertain significance Familial Mediterranean fever 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 653 of the MEFV protein (p.Arg653His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs104895085, ExAC 0.03%). This variant has been observed in several individuals affected with familial Mediterranean fever, however a second MEFV variant was identified in only one of these individuals (PMID: 11470495, 21413889, 24469716, 19479870, 16378925). 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: "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 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.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000255083 SCV001449978 likely pathogenic not provided 2019-12-12 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 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Counsyl RCV000002662 SCV001132429 likely pathogenic Familial Mediterranean fever 2019-03-15 no assertion criteria provided clinical testing

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