ClinVar Genomic variation as it relates to human health

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)

The MEFV c.586G>T; p.Gly196Trp variant (rs104895179) is reported in the literature in several individuals with periodic fever or autoimmune syndromes (Bozgeyik 2020, 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 are uncertain whether this variant is neutral or deleterious (REVEL: 0.237). 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: Bozgeyik E et al. Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics. Genomics. 2020 Jul;112(4):2755-2762. PMID: 32199921. 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.

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.

The MEFV c.586G>T variant is predicted to result in the amino acid substitution p.Gly196Trp. This variant has been reported in patients with Familial Mediterranean Fever (Jesus et al. 2012. PubMed ID: 22566169; Aydogan et al. 2013. PubMed ID: 23155201; Oztuzcu et al. 2014. PubMed ID: 24469716; Gunesacar et al. 2014. PubMed ID: 24929125; Bozgeyik et al. 2020. PubMed ID: 32199921) and systemic juvenile idiopathic arthritis (Cantarini et al. 2012. PubMed ID: 20044784). This variant is reported in 1.7% of alleles in individuals of African descent in gnomAD, including two homozygous individuals, which may be too common to be causative of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.