Submissions for variant NM_000243.3(MEFV):c.331G>A (p.Gly111Arg)

gnomAD frequency: 0.00014  dbSNP: rs112739451

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756333	SCV000884110	uncertain significance	not provided	2017-06-27	criteria provided, single submitter	clinical testing	The MEFV c.331G>A;p.Gly111Arg variant has been published in the medical literature in at least one individual with Crohn’s disease, but the variant was not described as causative and was also detected in their presumably unaffected parent (Villani 2009). The variant is listed in the dbSNP variant database (rs112739451) with an allele frequency of 0.03 percent (7/23228 alleles) in the African population in the Genome Aggregation Database. The variant is not listed in the ClinVar database. The amino acid at this position is moderately conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is tolerated. Taken together, there is insufficient information to classify this variant as benign or pathogenic with certainty. If this variant is later determined to be pathogenic, this individual would be predicted to a least be a carrier of familial Mediterranean fever (OMIM#608107). References: Villani AC et al. Genetic variation in the familial Mediterranean fever gene (MEFV) and risk for Crohn's disease and ulcerative colitis. PLoS One. 2009 Sep 28;4(9):e7154.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201760	SCV001372850	uncertain significance	Familial Mediterranean fever	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 111 of the MEFV protein (p.Gly111Arg). This variant is present in population databases (rs112739451, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of MEFV-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 618207). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Fulgent Genetics, Fulgent Genetics	RCV002477737	SCV002779127	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-09-20	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001201760	SCV003802416	benign	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126925	SCV003802417	benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126926	SCV003802418	benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001201760	SCV002087470	uncertain significance	Familial Mediterranean fever	2019-10-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535889	SCV004717385	uncertain significance	MEFV-related disorder	2024-02-07	no assertion criteria provided	clinical testing	The MEFV c.331G>A variant is predicted to result in the amino acid substitution p.Gly111Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.029% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.