ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.586G>T (p.Gly196Trp) (rs104895179)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000175563 SCV000227071 benign not specified 2015-04-03 criteria provided, single submitter clinical testing
GeneDx RCV000587560 SCV000279039 likely 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; This variant is associated with the following publications: (PMID: 29178647, 26990548, 22995991, 20044784, 24929125, 24263150, 32199921)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283563 SCV000604183 uncertain significance none provided 2020-07-01 criteria provided, single submitter clinical testing The MEFV c.586G>T; p.Gly196Trp variant (rs104895179) is reported in the literature in several individuals with periodic fever or autoimmune syndromes (Cantarini 2012, Oztuzcu 2014 ). However, the variant has also been reported in at least one individual with an alternate molecular explanation for disease (Gunesacar 2014). The variant is reported in the ClinVar database (Variation ID: 97532) and in the African population with an allele frequency of 1.7% (350/20,178 alleles including 2 homozygotes) in the Genome Aggregation Database. The glycine at codon 196 is weakly conserved and computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Although the allele frequency of this variant is higher than would be predicted for FMF, given the lack of clinical and functional data, the significance of the p.Gly196Trp variant is uncertain at this time. REFERENCES Cantarini L et al. Systemic-onset juvenile idiopathic arthritis complicated by early onset amyloidosis in a patient carrying a mutation in the MEFV gene. Rheumatol Int. 2012 Feb;32(2):465-7. Gunesacar R et al. Frequency of MEFV gene mutations in Hatay province, Mediterranean region of Turkey and report of a novel missense mutation (I247V). Gene. 2014 Aug 10;546(2):195-9 Oztuzcu S et al. Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep. 2014;41(4):2601-7.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587560 SCV000696076 uncertain significance not provided 2016-07-20 criteria provided, single submitter clinical testing Variant Summary: The MEFV variant, c.586G>T (p.Gly196Trp), causes a missense change involving a non-conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured here due to low reliability index value) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.20%, predominantly observed in the African subpopulation at a frequency of 2.4%. This frequency slightly exceeds the maximal expected allele frequency for a pathogenic variant in MEFV (2.2%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. The variant has been reported in the literature in at least 2 FMF patients, one of whom also had a common pathogenic mutation in the homozygous state (c.2082G>A, M694I; Gunesacar_2014), suggesting the variant of interest was not the causitive mutation in this individual. The variant has also been reported in atypical FMF patients and a Systemic Juvenile Idiopathic Arthritis patient, however the variant was the only detected variant in these patients. In addition, one reputable clinical lab has classified the variant as "benign", without evidence to independently evaluate. Taken together, this variant has been classified as a variant of uncertain significance, possibly benign variant, until additional information becomes available.
Invitae RCV000083784 SCV000753991 benign Familial Mediterranean fever 2020-11-23 criteria provided, single submitter clinical testing
Mendelics RCV000083784 SCV001139883 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083784 SCV000115882 not provided Familial Mediterranean fever no assertion provided not provided
Natera, Inc. RCV000083784 SCV001462424 likely benign Familial Mediterranean fever 2020-01-06 no assertion criteria provided clinical testing

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