ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.329T>C (p.Leu110Pro) (rs11466018)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000175565 SCV000227074 benign not specified 2014-10-14 criteria provided, single submitter clinical testing
GeneDx RCV000175565 SCV000279024 uncertain significance not specified 2016-05-13 criteria provided, single submitter clinical testing The L110P missense change has been observed in both the heterozygous and homozygous states in unaffected individuals and in patients with a clinical diagnosis of FMF (Kim et al., 2006; Tomiyama et al., 2008). Per the 1000 Genomes database, this variant has also been observed in 59/1008 alleles (5.9%) in the control East Asian population. In addition, L110P is nearly always present on the same allele (in cis) with E148Q. Therefore, it is not clear if this variant is a disease-associated variant with low penetrance and/or mild symptoms, or if it is a benign variant.
Integrated Genetics/Laboratory Corporation of America RCV000588731 SCV000696068 uncertain significance not provided 2017-08-18 criteria provided, single submitter clinical testing Variant summary: The MEFV c.329T>C (p.Leu110Pro) variant involves the alteration of non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 1711/273504 (66 homozygotes) control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.08558 (1606/18766). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. However, the variant 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). Large case-control studies are needed to validate these findings. ultiple clinical diagnostic laboratories have cited the variant with conflicting classifications "benign" or "uncertain significance." 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 is classified as Variant of Uncertain Significance (VUS), until additional information becomes available, specifically functional studies..
Invitae RCV000529898 SCV000629042 uncertain significance Familial Mediterranean fever 2018-01-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 110 of the MEFV protein (p.Leu110Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs11466018, ExAC 8%). In addition, there are a large number of homozygotes reported for this variant (ExAC 27 homozygotes). This variant has been reported in several individuals affected with familial Mediterranean fever (FMF), being found in the same chromosome as p.Glu148Gln in the vast majority of cases studied. This variant is commonly found in FMF patients in Japan, where it has been described at a higher frequency in affected individuals that in unaffected controls. However, the size of the samples used was small and the clinical significance of the data is uncertain (PMID: 10854105, 19531756, 24797171, 25073670, 27473114). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has been reported at high frequency in population databases, being shown to co-occur in the same chromosome with the well known MEFV variant, p.Glu148Gln, in FMF patients. However, three small studies report a higher frequency of this variant in affected individuals in Japan. This variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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