Submissions for variant NM_000243.3(MEFV):c.586G>T (p.Gly196Trp)

dbSNP: rs104895179

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	RCV000587560	SCV000604183	uncertain significance	not provided	2021-10-21	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 (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.
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	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000083784	SCV001139883	benign	Familial Mediterranean fever	2023-08-22	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731372	SCV001984445	uncertain significance	Familial Mediterranean fever, autosomal dominant	2020-07-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262648	SCV002542292	uncertain significance	Autoinflammatory syndrome	2020-05-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528779	SCV004109621	uncertain significance	MEFV-related disorder	2023-07-24	criteria provided, single submitter	clinical testing	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 (http://gnomad.broadinstitute.org/variant/16-3304482-C-A), 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.
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