ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1772T>C (p.Ile591Thr) (rs11466045)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589464 SCV000279052 benign not provided 2019-08-05 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; This variant is associated with the following publications: (PMID: 30476289, 29239128, 28748511, 29735907, 28191008, 29047407, 28386255, 28236224, 27943240, 28624931, 28302131, 28631068, 29178647, 28194777, 28158814, 27535533, 21228398, 16255051, 11464238, 17665427, 26299986, 20041150, 22995991, 16100353, 20721559, 12124996)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000214973 SCV000331572 likely benign not specified 2015-06-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000030178 SCV000396762 uncertain significance Familial Mediterranean fever 2018-01-25 criteria provided, single submitter clinical testing Across a selection of available literature, the MEFV c.1772T>C (p.Ile591Thr) missense variant has been identified in a total of 17 patients with familial Mediterranean fever (FMF), including in a compound heterozygous state in five patients and in a heterozygous state in twelve patients (Touitou 2001; Aldea et al. 2002; Tchernitchko et al. 2005; Fisher et al. 2005; Cañete et al. 2007; Ustek et al. 2008; Cornelius et al. 2011; Ait-Idir et al. 2011; Ceylan et al. 2012; Hernández-Rodríguez et al. 2016). Additionally, Aldea et al. (2002) reported the p.Ile591Thr variant in one affected individual in a compound heterozygous state with another known pathogenic variant. However, two siblings who also carried both of the identified variants were asymptomatic, suggesting that the p.Ile591Thr variant may not be disease-causing. This variant was found in six of 1310 control chromosomes (Aldea et al. 2002; Cañete et al. 2007; Ustek et al. 2008; Ait-Idir et al. 2011) and is reported at a frequency of 0.02336 in the Toscani in Italia population of the 1000 Genomes Project. Additionally, twenty three homozygotes are present in the Genome Aggregation Database. Based on the combined evidence, this variant does not appear to be disease-causing in the same manner as known pathogenic FMF variants, but some of the studies suggest that this variant may be a risk allele, modifier or mild allele that displays low penetrance. The p.Ile591Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for familial Mediterranean fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283567 SCV000604178 uncertain significance none provided 2020-08-31 criteria provided, single submitter clinical testing The MEFV c.1772T>C; p.Ile591Thr variant (rs11466045) has been reported in individuals with diagnosed or suspected Familial Mediterranean Fever (FMF) (Fisher 2005, Gumus 2018, Stella 2019, Touitou 2001), atypical FMF (Brown 2016), and also in individuals without FMF symptoms (Aldea 2002). Additionally, this variant has been identified in individuals with arthritis and fibromyalgia (Feng 2009, Canete 2007). This variant is reported with conflicting interpretations of pathogenicity by several laboratories in ClinVar (Variation ID: 36506), and it is found in the general population at an overall frequency of 1.1% (3,076/282,450 alleles, including 24 homozygotes) in the Genome Aggregation Database. The isoleucine at codon 591 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Although the population frequency of this variant is relatively high, the possibility of reduced penetrance or a mild effect cannot be excluded. Therefore, due to conflicting information and lack of functional data, the significance of this variant cannot be determined with certainty. References: Aldea A et al. I591T MEFV mutation in a Spanish kindred: is it a mild mutation, a benign polymorphism, or a variant influenced by another modifier? Hum Mutat. 2002; 20(2):148-50. Brown G et al. A baffling case of severe systemic inflammation. Putting the pieces together: genes, environment and triggers. Rheumatology (Oxford). 2017 May 1;56(5):853-854. Canete JD et al. An unexpectedly high frequency of MEFV mutations in patients with anti-citrullinated protein antibody-negative palindromic rheumatism. Arthritis Rheum. 2007; 56(8):2784-8. 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; 4(12):e8480. Fisher BA et al. Colchicine responsive periodic fever syndrome associated with pyrin I591T. Ann Rheum Dis. 2005; 64(9):1384-5. Gumus E. The Frequency of MEFV Gene Mutations and Genotypes in Sanliurfa Province, South-Eastern Region of Turkey, after the Syrian Civil War by Using Next Generation Sequencing and Report of a Novel Exon 4 Mutation (I423T). J Clin Med. 2018 May 7;7(5). pii: E105 Stella et al. Familial Mediterranean fever: breaking all the (genetic) rules. Rheumatology (Oxford). 2019 Mar 1;58(3):463-467. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001; 9(7):473-83.
Invitae RCV000030178 SCV000629030 likely benign Familial Mediterranean fever 2020-11-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000214973 SCV000696054 likely benign not specified 2021-02-16 criteria provided, single submitter clinical testing Variant summary: MEFV c.1772T>C (p.Ile591Thr) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. A recent report utilizing the meta predictor tool, REVEL (Rare Exome Variant Ensemble Learner) to assess the pathogenicity of MEFV variants with ambiguous classification proposed a likely benign outcome for this variant (Accetturo_2019). In this study, REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Auto Inflammatory Diseases. The variant allele was found at a frequency of 0.011 in 285086 control chromosomes, including 24 homozygotes (gnomAD and publication data). It was predominantly found within the European Finnish and non-Finnish subpopulations at a frequency of 0.021 and 0.017, respectively. These frequencies are close to the maximum expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.022). Additionally, the variant was reported with even higher frequencies in the 1000 Genomes Project within the British (0.022) and Toscani (Italian) (0.0234) subpopulation, suggesting this variant is likely a benign polymorphism found primarily in the populations of European origin. This variant has been mostly reported in heterozygous state in patients with Familial Mediterranean Fever (FMF), together with limited reports of compound heterozygosity in multiple ethnicities, without strong evidence for causality (e.g. Fisher 2005, Ait-Idir 2011, Lainka 2012, Papa 2017, Gumus 2018, Stella 2019). Additionally, in a Spanish family, the variant did not co-segregate with the disease, suggestive of an incomplete penetrance or a mostly benign impact (Aldea 2002). In a recent study the variant was found in heterozygous state in a cohort of FMF patients with a similar allele frequency (0.0113), as it was reported in controls in the gnomAD database (Balta_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (1x), VUS (4x), likely benign (3x) / benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589464 SCV000780522 uncertain significance not provided 2018-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197906 SCV001368689 uncertain significance Acute febrile neutrophilic dermatosis 2018-12-06 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4.
Nilou-Genome Lab RCV000030178 SCV001737225 likely benign Familial Mediterranean fever 2021-05-18 criteria provided, single submitter clinical testing
GeneReviews RCV000030178 SCV000484963 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Natera, Inc. RCV000030178 SCV001458296 benign Familial Mediterranean fever 2020-01-07 no assertion criteria provided clinical testing

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