Submissions for variant NM_000243.3(MEFV):c.2076_2078del (p.Ile692del)

dbSNP: rs104895093

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000487146	SCV000224796	pathogenic	not provided	2014-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000487146	SCV000565123	pathogenic	not provided	2023-02-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant has a deleterious effect on protein function (Honda et al., 2021); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19253030, 22975760, 23907647, 9668175, 10737995, 25648235, 26892483, 29543225, 32888943, 35812376, 19302049, 29379228, 28302131, 29047407, 17566872, 33733382)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487146	SCV001134280	pathogenic	not provided	2019-02-20	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Occurs in multiple cases with a recessive pathogenic variant in the same gene.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000487146	SCV001158041	pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	The MEFV c.2076_2078delAAT; p.Ile692del variant (rs104895093), is reported in the literature in multiple individuals affected with familial Mediterranean fever (FMF) (Aoki 2022, Bernot 1998, Platt 2021, Salehzadeh 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 97485), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single isoleucine residue leaving the rest of the protein in-frame. Functional analyses demonstrate increased cell death compared to wild-type, similar to other known pathogenic variants (Aoki 2022, Honda 2021). This variant affects a residue in the conserved region of the B30.2 domain, which contains pathogenic MEFV variants associated with the most severe FMF symptoms (Moradian 2017). Based on available information, the p.Ile692del variant is considered to be pathogenic. References: Aoki M et al. Case Report: A Pediatric Case of Familial Mediterranean Fever Concurrent With Autoimmune Hepatitis. Front Immunol. 2022 Jun 24;13:917398. PMID: 35812376. Bernot A et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. PMID: 9668175. Honda Y et al. Rapid Flow Cytometry-Based Assay for the Functional Classification of MEFV Variants. J Clin Immunol. 2021 Aug;41(6):1187-1197. PMID: 33733382. Moradian MM et al. Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF. Mol Genet Genomic Med. 2017 Nov;5(6):742-750. PMID: 29178647. Platt CD et al. Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency. J Allergy Clin Immunol. 2021 Feb;147(2):723-726. PMID: 32888943. Salehzadeh F et al. MEFV Gene Profile in Northwest of Iran, Twelve Common MEFV Gene Mutations Analysis in 216 Patients with Familial Mediterranean Fever. Iran J Med Sci. 2015 Jan;40(1):68-72. PMID: 25648235.
Invitae	RCV000083737	SCV001215382	uncertain significance	Familial Mediterranean fever	2019-11-26	criteria provided, single submitter	clinical testing	This variant, c.2076_2078del, results in the deletion of 1 amino acid(s) of the MEFV protein (p.Ile692del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with familial mediterranean fever (PMID: 29047407, 9668175, 21246368, 15018633, 22019805, 29379228, 25648235, 21413889, 28302131, 14578331, 19253030, 17566872). ClinVar contains an entry for this variant (Variation ID: 97485). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000487146	SCV001449622	pathogenic	not provided	2015-09-16	criteria provided, single submitter	clinical testing
3billion	RCV000083737	SCV002318574	pathogenic	Familial Mediterranean fever	2022-03-22	criteria provided, single submitter	clinical testing	nframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function(PM4_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000097485, PMID:9668175). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008). The variant is observed to be in trans with the other variant (3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262640	SCV002543731	pathogenic	Autoinflammatory syndrome	2022-03-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000487146	SCV003833988	likely pathogenic	not provided	2022-09-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000083737	SCV003922579	likely pathogenic	Familial Mediterranean fever	2023-03-20	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.2076_2078delAAT (p.Ile692del) results in an in-frame deletion that is predicted to remove one amino acid, Ile692, from the SPRY domain (IPR003877) of the encoded protein. The variant allele was found at a frequency of 7.9e-06 in 252200 control chromosomes (gnomAD and publications). c.2076_2078delAAT has been reported in the literature in the compound heterozygous and heterozygous state in multiple individuals affected with Familial Mediterranean Fever across several countries, including cases where it has been observed in trans with a pathogenic variant (e.g. Bernot_1998, Tchernitchko_2003, Medlej-Hashim_2005, Chaabouni_2007, Singh-Grewal_2007, Sabbagh_2008, El Garf_2010, Jardour_2010, Berdeli_2011, Salehzadeh_2015, Ait-Idir_2017). These data indicate that the variant is likely to be associated with disease. However, this variant mostly associates in cis with p.E148Q, a common variant with controversial pathogenicity and/or low penetrance and thus, there are fewer cases where the variant has been observed in isolation from which to definitively determine its association to the disease phenotype. At least one publication reports experimental evidence evaluating an impact of the variant on protein function (Honda_2021) and found that the variant was more responsive to TcdA- and UCN-01-induced cell death compared to the WT protein, suggesting it has an effect on protein function, yet the significance of this finding in a clinical context are not clear. Therefore this study does not allow for unequivocal conclusions about the variant effect. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=5)/likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic until further evidence (i.e. homozygous occurrences in patients, cosegregation of the variant with FMF and/or additional functional studies) is available.
Baylor Genetics	RCV003460764	SCV004194414	pathogenic	Familial Mediterranean fever, autosomal dominant	2023-08-14	criteria provided, single submitter	clinical testing
OMIM	RCV000083737	SCV000022813	pathogenic	Familial Mediterranean fever	1998-08-01	no assertion criteria provided	literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083737	SCV000115830	not provided	Familial Mediterranean fever		no assertion provided	not provided
GeneReviews	RCV000083737	SCV000484967	not provided	Familial Mediterranean fever		no assertion provided	literature only
Counsyl	RCV000083737	SCV001132430	likely pathogenic	Familial Mediterranean fever	2019-03-15	no assertion criteria provided	clinical testing