ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.329T>C (rs11466018)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000175565 SCV000227074 benign not specified 2014-10-14 criteria provided, single submitter clinical testing
GeneDx RCV000588731 SCV000279024 benign not provided 2019-07-03 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in both the heterozygous and homozygous states in unaffected individuals and in individuals with familial Mediterranean fever (Kim et al., 2006; Tomiyama et al., 2008); This variant is associated with the following publications: (PMID: 24965843, 17329916, 22989844, 23166428, 24797171, 24598070, 10854105, 24929125, 20041150, 25073670, 22534884, 26332735, 29017770, 28482392, 29178647, 26537665, 19967574, 18328141, 25261100, 29642170, 26457478, 29526930, 29151129, 24661635, 32199921, 32735870)
Invitae RCV001083220 SCV000629042 likely benign Familial Mediterranean fever 2020-12-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000175565 SCV000696068 uncertain significance not specified 2019-06-10 criteria provided, single submitter clinical testing Variant summary: MEFV c.329T>C (p.Leu110Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0066 in 247318 control chromosomes, predominantly at a frequency of 0.084 within the East Asian subpopulation in the gnomAD database, including 61 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MEFV causing Familial Mediterranean Fever phenotype (0.022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. However, the variant c.329T>C has also been commonly reported in FMF patients, primarily in the same allele (in cis) with p.E148Q, both in heterozygote and homozygote phases. In addition, multiple publications show lack of cosegregation for the variant and disease (Oshima_2010, Berdeli_2011, and Kim_2007). In Japanese population, the variant's allele frequency is higher in patients than in controls. Case-control studies in Japanese population indicate this variant may associate with increased risk of FMF (OR= 1.78, Migita_2016; OR=4.81, Tsuchiya-Suzuki_2009). Larger case-control studies are needed to validate these findings. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VYS (2x) or likely benign (1x). Based on the data available at this time, it is unknown whether this variant represents a low penetrance mild common pathogenic variant, modifier, or a risk allele. Therefore, this variant was classified as uncertain significance, until additional information becomes available.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000588731 SCV000884107 likely benign not provided 2017-07-18 criteria provided, single submitter clinical testing The MEFV c.329T>C;p.Leu110Pro variant (rs11466018) is listed in the Genome Aggregation Database with an allele frequency of up to 8.558 percent (1606/18766 alleles, with 66 homozygotes) in East Asians. The variant is listed in the ClinVar database (Variation ID: 195050). The amino acid at this position is weakly conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is tolerated. Although this variant has been published in individuals with periodic fever and related disorders (Feng 2009, Fujikawa 2014, Lim 2012, Migita 2014), this variant is considered likely benign based on the relatively high population frequency. 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 Dec 30;4(12):e8480. Fujikawa K et al. MEFV gene polymorphisms and TNFRSF1A mutation in patients with inflammatory myopathy with abundant macrophages. Clin Exp Immunol. 2014 Nov;178(2):224-8. Lim AL et al. Familial Mediterranean fever: the first adult case in Korea. J Korean Med Sci. 2012 Nov;27(11):1424-7. Migita K et al. Familial Mediterranean fever: genotype-phenotype correlations in Japanese patients. Medicine (Baltimore). 2014 May;93(3):158-64.
Illumina Clinical Services Laboratory,Illumina RCV001083220 SCV001277846 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000588731 SCV001450092 likely pathogenic not provided 2014-07-10 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV001083220 SCV001653449 uncertain significance Familial Mediterranean fever 2021-05-18 criteria provided, single submitter clinical testing
Natera, Inc. RCV001083220 SCV001462431 uncertain significance Familial Mediterranean fever 2020-01-07 no assertion criteria provided clinical testing

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