ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.2164G>A (p.Val722Met) (rs104895201)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000083752 SCV001139812 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000083752 SCV001216566 uncertain significance Familial Mediterranean fever 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 722 of the MEFV protein (p.Val722Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs104895201, ExAC 0.004%). This variant has been observed in individuals affected with Behcet's disease and familial Mediterranean fever (PMID: 18609258, 21413889, 24469716). ClinVar contains an entry for this variant (Variation ID: 97500). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Illumina Clinical Services Laboratory,Illumina RCV000083752 SCV001277620 uncertain significance Familial Mediterranean fever 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV001175016 SCV001338530 uncertain significance not specified 2020-04-17 criteria provided, single submitter clinical testing Variant summary: MEFV c.2164G>A (p.Val722Met) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2164G>A has been reported in the literature in individuals affected with Behcet's disease (Ayesh_2008, Kirino_2013) and Familial Mediterranean Fever (Berdeli_2011, Oztuzcu_2014, Erken_2015), however it was also observed in controls (Kirino_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The variant has been reported by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) with an experts consensus as "VUS" (Van Gijn_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083752 SCV000115846 not provided Familial Mediterranean fever no assertion provided not provided

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