Submissions for variant NM_000243.3(MEFV):c.2040G>C (p.Met680Ile)

dbSNP: rs28940580

Total submissions: 39

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030179	SCV000052839	pathogenic	Familial Mediterranean fever	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Eurofins Ntd Llc (ga)	RCV000222364	SCV000224797	pathogenic	not provided	2014-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000222364	SCV000279057	pathogenic	not provided	2022-09-06	criteria provided, single submitter	clinical testing	Accounts for approximately 9% of identifiable pathogenic MEFV variants in patients of different ethnic groups (Aksentijevich et al., 1999); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20483145, 27621632, 19967574, 10447272, 16179998, 24433404, 16785446, 30513227, 27457448, 29080837, 19302049, 33440462, 10852276, 20669279, 23973724, 20437121, 21623663, 9288758, 19863562, 24141617, 10364520, 10090880, 23907647, 27513391, 12908875, 19151977, 26510601, 28492532, 29543225, 30783801, 32199921, 34426522, 31589614, 11977178, 32441320, 10662876)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000222364	SCV000604173	pathogenic	not provided	2024-07-24	criteria provided, single submitter	clinical testing	The MEFV c.2040G>C;p.Met680Ile variant has been published as a common familial Mediterranean fever pathogenic variant (Moradian 2014, The International FMF Consortium 1997). The variant is listed in the dbSNP variant database (rs28940580) with an allele frequency of 0.009 percent overall in the Exome Aggregation Consortium and 0.0077 percent in the Exome Variant Server. Taken together, this variant is considered pathogenic. References: Moradian MM et al. (2014) Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 16(3):258-63. The International FMF Consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 90:797-807.
Fulgent Genetics, Fulgent Genetics	RCV002477026	SCV000611205	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2024-03-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000030179	SCV000629033	pathogenic	Familial Mediterranean fever	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 680 of the MEFV protein (p.Met680Ile). This variant is present in population databases (rs28940580, gnomAD 0.02%). This missense change has been observed in individual(s) with symptoms of familial Mediterranean fever (PMID: 9288758, 21623663, 23907647, 23973724). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36507). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222364	SCV001134279	pathogenic	not provided	2019-02-20	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a tolerated effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
CeGaT Center for Human Genetics Tuebingen	RCV000222364	SCV001245671	pathogenic	not provided	2025-02-01	criteria provided, single submitter	clinical testing	MEFV: PM3:Very Strong, PS1, PM5, PM2:Supporting, PS3:Supporting, BP4
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197705	SCV001368484	pathogenic	Acute febrile neutrophilic dermatosis	2020-02-25	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM3,PM5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000222364	SCV001447340	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV002254152	SCV001448269	pathogenic	Familial Mediterranean fever, autosomal dominant	2020-10-04	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000222364	SCV001449578	pathogenic	not provided	2014-10-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000030179	SCV001810498	pathogenic	Familial Mediterranean fever	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000222364	SCV002024334	pathogenic	not provided	2020-10-16	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000030179	SCV002059616	pathogenic	Familial Mediterranean fever	2021-08-12	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251932	SCV002523125	pathogenic	See cases	2021-04-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2, PM3, BP4
Department of Human Genetics, Hannover Medical School	RCV002254152	SCV002525496	pathogenic	Familial Mediterranean fever, autosomal dominant	2022-06-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262586	SCV002543729	pathogenic	Autoinflammatory syndrome	2022-02-08	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000030179	SCV002577425	pathogenic	Familial Mediterranean fever	2022-07-18	criteria provided, single submitter	clinical testing	PS1, PS3, PM1, PM5, PM2, PP5, BP4
MGZ Medical Genetics Center	RCV000030179	SCV002580913	pathogenic	Familial Mediterranean fever	2022-06-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415433	SCV002723049	pathogenic	Inborn genetic diseases	2018-01-11	criteria provided, single submitter	clinical testing	The p.M680I pathogenic mutation (also known as c.2040G>C), located in coding exon 10 of the MEFV gene, results from a G to C substitution at nucleotide position 2040. The methionine at codon 680 is replaced by isoleucine, an amino acid with highly similar properties. This mutation is well documented as one of the five most common MEFV mutations and has been seen in both the homozygous and heterozygous states in multiple individuals with a clinical diagnosis of familial Mediterranean fever (FMF). In addition, codon 680 in the MEFV gene has been documented as a mutational hotspot and is associated with severe manifestations of FMF (Neocleous V et al. Ann. Hum. Genet., 2015 Jan;79:20-7; Touitou I. Eur. J. Hum. Genet., 2001 Jul;9:473-83; The International FMF Consortium. Cell, 1997 Aug;90:797-807). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000030179	SCV004013446	pathogenic	Familial Mediterranean fever	2023-07-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002254152	SCV004194411	pathogenic	Familial Mediterranean fever, autosomal dominant	2024-03-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000222364	SCV004226903	pathogenic	not provided	2024-09-09	criteria provided, single submitter	clinical testing	PM1, PS3, PS4
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000030179	SCV004847543	pathogenic	Familial Mediterranean fever	2022-11-03	criteria provided, single submitter	clinical testing	The p.Met680Ile variant in MEFV has been reported in the homozygous and compound heterozygous state in numerous individuals with familial Mediterranean fever and accounts for approximately 9% of pathogenic MEFV variants in individuals of different ethnic groups (example: Aksentijevich 1999 PMID: 10090880). It has been reported in ClinVar (Variation ID 36507) and has been identified in 6/68036 European chromosomes by gnomAD ((http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive familial Mediterranean fever. ACMG/AMP Criteria applied: PM2_Supporting, PM3_VeryStrong, PP1_Strong.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000222364	SCV005198751	pathogenic	not provided	2022-10-06	criteria provided, single submitter	clinical testing
OMIM	RCV000030179	SCV000022808	pathogenic	Familial Mediterranean fever	1999-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000030179	SCV000484965	not provided	Familial Mediterranean fever		no assertion provided	literature only
Counsyl	RCV000030179	SCV001132428	pathogenic	Familial Mediterranean fever	2019-03-15	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000030179	SCV001462099	pathogenic	Familial Mediterranean fever	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000222364	SCV001741393	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000222364	SCV001807652	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000222364	SCV001930242	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000222364	SCV001959280	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000222364	SCV001973052	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	RCV000030179	SCV002573424	pathogenic	Familial Mediterranean fever	2022-05-01	no assertion criteria provided	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000222364	SCV002818117	pathogenic	not provided	2022-12-17	flagged submission	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000030179	SCV004101055	pathogenic	Familial Mediterranean fever	2023-11-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739312	SCV005347588	pathogenic	MEFV-related disorder	2024-03-06	no assertion criteria provided	clinical testing	The MEFV c.2040G>C variant is predicted to result in the amino acid substitution p.Met680Ile. This variant, in the homozygous, compound heterozygous and heterozygous states, has been reported to be causative for familial Mediterranean fever (Int. FMF. et al. 1997. PubMed ID: 9288758; Moradian et al. 2014. PubMed ID: 23907647). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.