Submissions for variant NM_000243.3(MEFV):c.775A>G (p.Ile259Val)

gnomAD frequency: 0.00004  dbSNP: rs104895144

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587366	SCV000696079	uncertain significance	not provided	2016-03-22	criteria provided, single submitter	clinical testing	Variant summary: The variant c.775A>G (p.Ile259Val) affects a non-conserved nucleotide and results in replacement of Valine with an Isoleucine. Both amino acids are medium size and hydrophobic and therefore this substitution likely does not change the physico-chemical property of the protein. 5/5 in silico tools predict benign outcome for this change. The variant was found in the large and broad cohorts of the NHLBI-ES and ExAC projects at an allele frequency of 0.0025% which does not exceed the maximal expected allele frequency for a disease-causing MEFV variant (2.17%). However, the possibility that this variant may still represent as a rare polymorphism cannot be ruled out. There are a few patients with symptoms of FMF reported in the literature who carried the variant; however, most of these patient reports lack detailed clinical phenotypic data. Importantly, one patient with symptoms of FMF also carried p. M694V in homozygous state, indicating this variant may not be pathogenic or it acts as modifier of the pathogenic variant p.M694V. The variant p.M694V is known to be a highly penetrant pathogenic variant. Deletion of p.M694 has been shown to be causal for dominant FMF which also highlights the importance of p.M694 residue. There are no in vivo/vitro studies to describe the functional impact of the variant till date. Infevers database lists variant in one Turkish patient with a classification of VUS (unknown consequence) and HGMD lists variant with a classification of "Disease-Mutation". In summary, collective evidence suggests that this variant is unlikely to be pathogenic and it was classified as a VUS-possibly benign until more information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000083797	SCV000959513	uncertain significance	Familial Mediterranean fever	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 259 of the MEFV protein (p.Ile259Val). This variant is present in population databases (rs104895144, gnomAD 0.006%). This missense change has been observed in individual(s) with however, in one of these individuals, a homozygous pathogenic allele was also identified in MEFV, which suggests this c.775A>G variant was not the primary cause of disease and/or Mediterranean fever (PMID: 22614345, 24469716, 25626331, 31989427). ClinVar contains an entry for this variant (Variation ID: 97545). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics	RCV000083797	SCV001139874	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000132	SCV001156581	uncertain significance	not specified	2018-11-14	criteria provided, single submitter	clinical testing	The MEFV c.775A>G; p.Ile259Val variant (rs104895144), is reported in the literature in the heterozygous state in individuals affected with familial mediterranean fever (Ceylan 2012, Oztuzcu 2014, Tzifi 2014). This variant is reported in ClinVar (Variation ID: 97545), and is found in the general population with an overall allele frequency of 0.0032% (8/251,446 alleles) in the Genome Aggregation Database. The isoleucine at codon 259 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Ile259Val variant is uncertain at this time. References: Ceylan GG et al. Frequency of alterations in the MEFV gene and clinical signs in familial Mediterranean fever in Central Anatolia, Turkey. Genet Mol Res. 2012 May 7;11(2):1185-94. 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. Tzifi F et al. Acute hepatitis in a child heterozygous for the I259V MEFV gene variant. Prague Med Rep. 2014;115(3-4):128-33.
Illumina Laboratory Services, Illumina	RCV000083797	SCV001274514	uncertain significance	Familial Mediterranean fever	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262654	SCV002542304	uncertain significance	Autoinflammatory syndrome	2021-11-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505014	SCV002816140	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-12-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000083797	SCV003802276	likely benign	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126485	SCV003802277	benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126486	SCV003802279	benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529876	SCV004115245	uncertain significance	MEFV-related disorder	2023-06-02	criteria provided, single submitter	clinical testing	The MEFV c.775A>G variant is predicted to result in the amino acid substitution p.Ile259Val. This variant has been reported in five patients with familial Mediterranean fever (FMF), although segregation data was not presented in any of these cases and one patient was also homozygous for a different pathogenic variant (Ceylan et al. 2012. PubMed ID: 22614345; Oztuzcu et al. 2014. PubMed ID: 24469716; Tzifi et al. 2014. PubMed ID: 25626331; Balta et al. 2020. PubMed ID: 31989427). This variant was also reported in a patient with early coronary heart disease (Basar et al. 2014. PubMed ID: 24702757). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3304293-T-C). 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	RCV000083797	SCV000115895	not provided	Familial Mediterranean fever		no assertion provided	not provided
Natera, Inc.	RCV000083797	SCV002087436	uncertain significance	Familial Mediterranean fever	2020-01-20	no assertion criteria provided	clinical testing