ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1061G>A (p.Arg354Gln) (rs763015849)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588244 SCV000696039 uncertain significance not provided 2016-08-19 criteria provided, single submitter clinical testing Variant summary: The MEFV c.1061G>A (p.Arg354Gln) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 10/119332 control chromosomes at a frequency of 0.0000838, predominantly in individuals of South Asian descent (0.000429; 7/16316 chrs tested). These frequencies do not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). This variant has been reported in a patient with probable FMF without strong evidence for causality. The variant of interest has not, to our knowledge, been reported in affected individuals via clinical diagnostic laboratories nor was it evaluated for a functional impact by in vivo/vitro studies. Due to the lack of clinical information and absence of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000632792 SCV000753980 uncertain significance Familial Mediterranean fever 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 354 of the MEFV protein (p.Arg354Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs763015849, ExAC 0.04%). This variant has been reported in several individuals affected with familial mediterranean fever (FMF) (PMID: 24797171, 25974247, 27473114). 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 glutamine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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