ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1437C>G (p.Phe479Leu) (rs104895083)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282846 SCV000604190 pathogenic none provided 2020-08-25 criteria provided, single submitter clinical testing The MEFV c.[501G>C;1437C>G]; p.[Glu167Asp;Phe479Leu] variant is a complex allele consisting of two changes on the same chromosome, p.Glu167Asp and p.Phe479Leu. Although p.Phe479Leu has been reported on its own, to the best of our knowledge p.Glu167Asp has only been reported as a complex allele with p.Phe479Leu. The complex variant has been published in the literature in both the homozygous and compound heterozygous state in individuals affected with familial Mediterranean fever (Bernot 1998, Bonyadi 2009, Mansour 2001, Neocleous 2015) and is one of the most common pathogenic MEFV variants in the Cypriot populations (Neocleous 2015). Based on available information, this variant is considered to be pathogenic. References: Bernot A et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. Bonyadi M et al. MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever. Clin Genet. 2009 Nov;76(5):477-80. Mansour I et al. Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations. Eur J Hum Genet. 2001 Jan;9(1):51-5. Neocleous V et al. Familial Mediterranean fever associated with MEFV mutations in a large cohort of Cypriot patients. Ann Hum Genet. 2015 Jan;79(1):20-7
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508324 SCV001134277 pathogenic not provided 2019-02-20 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/282890 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Statistically enriched in patients compared to ethnically matched controls.
Mendelics RCV000002654 SCV001139854 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000508324 SCV001245674 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Invitae RCV000002654 SCV001416538 uncertain significance Familial Mediterranean fever 2019-08-29 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 479 of the MEFV protein (p.Phe479Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs104895083, ExAC 0.006%). This variant has been observed frequently in cis (on the same chromosome) with the MEFV p.Glu167Asp variant in individuals with MEFV-related disorders with variable phenotypes and a wide range of severity (including asymptomatic individuals) (PMID: 9668175, 11175300, 25708585, 25393764, 22975760, 23907647, 26351556, 29363386, 29178647). In some of these individuals, an additional MEFV variant was not identified on the opposite allele, while in others, multiple additional MEFV variants were identified. Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 2545). 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 leucine 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, this variant has been reported in many affected individuals as well as in unaffected individuals. However, 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.
Hadassah Hebrew University Medical Center RCV000002654 SCV001437668 pathogenic Familial Mediterranean fever 2019-06-20 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000508324 SCV001449673 likely pathogenic not provided 2017-01-11 criteria provided, single submitter clinical testing
OMIM RCV000002654 SCV000022812 pathogenic Familial Mediterranean fever 2009-11-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000002654 SCV000115785 not provided Familial Mediterranean fever no assertion provided not provided
Natera, Inc. RCV000002654 SCV001452073 pathogenic Familial Mediterranean fever 2020-09-16 no assertion criteria provided clinical testing

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