Submissions for variant NM_000243.3(MEFV):c.2160C>G (p.Ile720Met)

gnomAD frequency: 0.00001  dbSNP: rs104895102

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000083751	SCV000818062	uncertain significance	Familial Mediterranean fever	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 720 of the MEFV protein (p.Ile720Met). This variant is present in population databases (rs104895102, gnomAD 0.002%). This missense change has been observed in individual(s) with familial Mediterranean fever (FMF) (PMID: 11903360, 21413889). ClinVar contains an entry for this variant (Variation ID: 97499). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780406	SCV000917628	uncertain significance	not specified	2018-06-04	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.2160C>G (p.Ile720Met) results in a conservative amino acid change located in the B30.2/SPRY domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246466 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2160C>G has been reported in the literature in numerous individuals affected with Familial Mediterranean Fever, and most of these reports are in heterozygous patients, suggesting this variant may cause the dominant form of Familial Mediterranean Fever. However, strong evidence, such as cosegregation analysis within families, was not reported in these studies. Thus, these reports do not provide unequivocal conclusions about association of the variant with Dominant Familial Mediterranean Fever. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until more information becomes available.
Mendelics	RCV000083751	SCV001139813	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000083751	SCV001279827	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-Nilou Lab	RCV000083751	SCV003802556	benign	Familial Mediterranean fever	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126451	SCV003802567	benign	Familial Mediterranean fever, autosomal dominant	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003126452	SCV003802578	benign	Acute febrile neutrophilic dermatosis	2023-02-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529874	SCV004116945	uncertain significance	MEFV-related disorder	2023-05-11	criteria provided, single submitter	clinical testing	The MEFV c.2160C>G variant is predicted to result in the amino acid substitution p.Ile720Met. This variant was reported in an individual with Mediterranean fever, familial (Medlej-Hashim et al 2002. PubMed ID: 11903360). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3293327-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000083751	SCV004808187	uncertain significance	Familial Mediterranean fever	2024-03-29	criteria provided, single submitter	clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083751	SCV000115845	not provided	Familial Mediterranean fever		no assertion provided	not provided
Natera, Inc.	RCV000083751	SCV002093881	uncertain significance	Familial Mediterranean fever	2020-07-29	no assertion criteria provided	clinical testing