Submissions for variant NM_000243.3(MEFV):c.1744A>C (p.Met582Leu)

gnomAD frequency: 0.00001  dbSNP: rs104895165

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000083708	SCV000965094	uncertain significance	Familial Mediterranean fever	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 582 of the MEFV protein (p.Met582Leu). This variant is present in population databases (rs104895165, gnomAD 0.003%). This missense change has been observed in individual(s) with palindromic rheumatism (PMID: 17665427). ClinVar contains an entry for this variant (Variation ID: 97456). 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 leucine 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	RCV000083708	SCV001139845	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262634	SCV002543718	uncertain significance	Autoinflammatory syndrome	2021-04-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483161	SCV002780058	uncertain significance	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2022-04-19	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000083708	SCV003802057	uncertain significance	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126433	SCV003802058	likely benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126434	SCV003802059	likely benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488380	SCV004241235	uncertain significance	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.1744A>C (p.Met582Leu) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251428 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1744A>C has been reported in the literature as a single heterozygous change in one individual affected with AntiCitrullinated Protein Antibody Negative Palindromic Rheumatism (example, Canete_2007), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 17665427). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=6, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083708	SCV000115799	not provided	Familial Mediterranean fever		no assertion provided	not provided
Natera, Inc.	RCV000083708	SCV002087388	uncertain significance	Familial Mediterranean fever	2021-06-29	no assertion criteria provided	clinical testing