Submissions for variant NM_000243.3(MEFV):c.1061G>A (p.Arg354Gln)

gnomAD frequency: 0.00002  dbSNP: rs763015849

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588244	SCV000696039	uncertain significance	not provided	2016-08-19	criteria provided, single submitter	clinical testing	Variant summary: The MEFV c.1061G>A (p.Arg354Gln) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 10/119332 control chromosomes at a frequency of 0.0000838, predominantly in individuals of South Asian descent (0.000429; 7/16316 chrs tested). These frequencies do not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). This variant has been reported in a patient with probable FMF without strong evidence for causality. The variant of interest has not, to our knowledge, been reported in affected individuals via clinical diagnostic laboratories nor was it evaluated for a functional impact by in vivo/vitro studies. Due to the lack of clinical information and absence of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632792	SCV000753980	uncertain significance	Familial Mediterranean fever	2022-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 354 of the MEFV protein (p.Arg354Gln). This variant is present in population databases (rs763015849, gnomAD 0.04%). This missense change has been observed in individual(s) with familial Mediterranean fever (FMF) (PMID: 24797171, 25974247, 27473114). ClinVar contains an entry for this variant (Variation ID: 495749). 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 glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263819	SCV002543686	uncertain significance	Autoinflammatory syndrome	2018-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476271	SCV002791500	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-11-23	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000632792	SCV003802214	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001276301	SCV003802215	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126829	SCV003802216	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001276301	SCV001462421	uncertain significance	Familial Mediterranean fever, autosomal dominant	2020-06-17	no assertion criteria provided	clinical testing