ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.986G>A (p.Arg329His) (rs104895112)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000585083 SCV000604184 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing The MEFV c.986G>A; p.Arg329His variant (rs104895112) has been described in the literature in one individual with fibromyalgia (Feng 2009), but has not been described in individuals with Familial Mediterranean Fever. This variant is listed in ClinVar (Variation ID: 97557) and observed in the Genome Aggregation Database with an allele frequency of 0.16 % (428/274062 alleles, 2 homozygotes). The arginine at position 329 is weakly conserved (Alamut v2.10) and a histidine is found in at least two mammals. Additionally, computational programs (SIFT, PolyPhen2, MutationTaster) predict this variant has minimal impact on MEFV protein structure or function. Due to the limited information regarding the p.Arg329His variant, its clinical significance could not be determined with certainty. References: Feng J et al. Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels. PLoS One. 2009. 4(12):e8480.
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735285 SCV000854438 uncertain significance Cryptorchidism; Global developmental delay; Seizures; Abnormality of the anterior fontanelle; Macrocephalus; Deep plantar creases; Abnormality of the cerebral white matter; Central hypotonia criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585083 SCV000692832 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000585083 SCV000338237 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing
GeneDx RCV000585083 SCV000279045 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing The R329H variant in the MEFV gene has been reported previously in the heterozygous state in multiple unrelated individuals with familial Mediterranean fever (Feng et al., 2009; Lainka et al., 2012; Yao et al., 2015). This variant is observed in 111/10,054 alleles (1.1%) from individuals of Ashkenazi Jewish background, and 428/274,062 global alleles (0.16%), in large population cohorts including 2 homozygous control individuals (Lek et al., 2016). The R329H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret R329H as a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000585083 SCV000696084 uncertain significance not provided 2017-03-21 criteria provided, single submitter clinical testing Variant summary: The MEFV c.986G>A (p.Arg329His) variant located in the Zinc finger domain (via Interpro) involves the alteration of a non-conserved nucleotide and 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. This variant was found in 197/121354 control chromosomes (2 homozygotes) at a frequency of 0.0016233, which does not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. In the literature, the variant has been reported in patients with symptoms suggestive of FMF, atypical FMF, MS and fibromyalgia. Since the phenotypic variability seen with this variant and genotypic information are not purely specific to FMF, and several FMF patients reported in the literature were not responsive to colchicine therapy, this variant has been classified as a "Variant of Uncertain Significance".
Invitae RCV000083809 SCV000629050 uncertain significance Familial Mediterranean fever 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 329 of the MEFV protein (p.Arg329His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs104895112, ExAC 0.2%). This variant has been reported in individuals affected with familial Mediterranean fever (FMF) and is associated with atypical phenotypes (PMID: 26620106, 23070486, 26554556). ClinVar contains an entry for this variant (Variation ID: 97557). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000083809 SCV000782513 uncertain significance Familial Mediterranean fever 2016-10-28 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083809 SCV000115910 not provided Familial Mediterranean fever no assertion provided not provided

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