VCV000036507.104 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(39)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 36507 Accession: VCV000036507.104

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 3243447 (GRCh38) [ NCBI UCSC ] 16: 3293447 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000243.3:c.2040G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000234.1:p.Met680Ile	missense
NM_001198536.2:c.*244G>C		3 prime UTR
NC_000016.10:g.3243447C>G
NC_000016.9:g.3293447C>G
NG_007871.1:g.18181G>C
LRG_190:g.18181G>C
LRG_190t1:c.2040G>C	LRG_190p1:p.Met680Ile
	O15553:p.Met680Ile

... more HGVS ... less HGVS

Protein change

Other names

MEFV, MET680ILE, 2040G-C
M680I

Canonical SPDI

NC_000016.10:3243446:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00006

Links

ClinGen: CA280267 UniProtKB: O15553#VAR_028343 OMIM: 608107.0004 dbSNP: rs28940580 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MEFV		No evidence available	No evidence available	GRCh38 GRCh37	960	1261
LOC126862264	-	-	-	GRCh38	-	257

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Familial Mediterranean fever	Pathogenic (14)	criteria provided, multiple submitters, no conflicts	Jan 22, 2024	RCV000030179.35
not provided	Pathogenic (16)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000222364.67
Acute febrile neutrophilic dermatosis	Pathogenic (1)	criteria provided, single submitter	Feb 25, 2020	RCV001197705.10
Familial Mediterranean fever Familial Mediterranean fever, autosomal dominant	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV000515335.15
See cases	Pathogenic (1)	criteria provided, single submitter	Apr 6, 2021	RCV002251932.9
Familial Mediterranean fever, autosomal dominant	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV002254152.11
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jan 11, 2018	RCV002415433.9
Acute febrile neutrophilic dermatosis Familial Mediterranean fever Familial Mediterranean fever, autosomal dominant	Pathogenic (1)	criteria provided, single submitter	Apr 8, 2022	RCV002477026.8
Autoinflammatory syndrome	Pathogenic (1)	criteria provided, single submitter	Feb 8, 2022	RCV002262586.10
MEFV-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 6, 2024	RCV004739312.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
pathogenic (Aug 18, 2011)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: curation, clinical testing	Familial Mediterranean Fever (autosomal recessive) Affected status: unknown, yes Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052839.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022	Publications: PubMed (20) PubMed: 10024914‚ 12105243‚ 11017802‚ 10737995‚ 16439335‚ 12401847‚ 10612841‚ 10090880‚ 17331080‚ 10905662‚ 20534143‚ 16255051‚ 10364520‚ 14727057‚ 17489852‚ 10447272‚ 12687559‚ 11938447‚ 19967574‚ 9288758 Comment: Converted during submission to Pathogenic. Observation 1: Number of individuals with the variant: 2 Observation 2: Number of individuals with the variant: 13 Observation 3: Number of individuals with the variant: 2 Observation 4: Number of individuals with the variant: 24 Observation 5: Tissue: Blood Observation 6: Tissue: Blood Observation 7: Tissue: Blood Observation 8: Tissue: Blood Observation 9: Tissue: Blood Observation 10: Tissue: Blood Observation 11: Tissue: Blood
Pathogenic (Oct 14, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000224797.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MEFV Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal unknown) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447340.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Fever (present) , Recurrent fever (present) , Episodic abdominal pain (present) Sex: male
Pathogenic (Feb 20, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001134279.3 First in ClinVar: Jan 06, 2020 Last updated: Jan 03, 2022	Publications: PubMed (15) PubMed: 9288758‚ 26510601‚ 27513391‚ 20669279‚ 16179998‚ 21623663‚ 12908875‚ 23907647‚ 20437121‚ 19967574‚ 23973724‚ 20483145‚ 19151977‚ 21600797‚ 15951859 Comment: 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 … (more) 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. (less)
Pathogenic (Jul 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV002577425.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Comment: PS1, PS3, PM1, PM5, PM2, PP5, BP4
Pathogenic (Jun 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580913.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4, PM3_STR, PS3_MOD, PM1, PP1	Number of individuals with the variant: 3 Sex: female
Pathogenic (Sep 06, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279057.13 First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000629033.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 28492532‚ 9288758‚ 21623663‚ 23907647‚ 23973724 Comment: 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). … (more) 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. (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004194411.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001245671.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: MEFV: PM3:Very Strong, PS1, PM5, PM2:Supporting, PS3:Supporting, BP4 Number of individuals with the variant: 51
Pathogenic (Oct 01, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449578.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 31
Pathogenic (Feb 25, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acute febrile neutrophilic dermatosis Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368484.2 First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM3,PM5.
Pathogenic (Jul 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001810498.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Sex: mixed
Pathogenic (Aug 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059616.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Apr 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523125.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: ACMG classification criteria: PS3, PS4, PM2, PM3, BP4 Clinical Features: Inflammation of the large intestine (present) , Failure to thrive (present) , Bloody diarrhea (present) , Anemia (present) , Abdominal pain (present)
Pathogenic (Jun 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Department of Human Genetics, Hannover Medical School Accession: SCV002525496.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Clinical Features: Fever (present)
Pathogenic (Feb 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammatory syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002543729.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Pathogenic (Apr 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Familial Mediterranean fever Acute febrile neutrophilic dermatosis Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611205.2 First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022
Pathogenic (Dec 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818117.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023
Pathogenic (Sep 14, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604173.7 First in ClinVar: Sep 30, 2017 Last updated: Mar 04, 2023	Comment: The MEFV c.2040G>C; p.Met680Ile variant (rs28940580) has been published as a common familial Mediterranean fever pathogenic variant (Moradian 2014, The International FMF Consortium 1997). This … (more) The MEFV c.2040G>C; p.Met680Ile variant (rs28940580) has been published as a common familial Mediterranean fever pathogenic variant (Moradian 2014, The International FMF Consortium 1997). This variant is also reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 36507). It is found in the general population with an overall allele frequency of 0.01% (26/251474 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Moradian MM et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 2014; 16(3):258-63. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997; 90:797-807. (less)
Pathogenic (Jul 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever (Autosomal recessive inheritance) Affected status: no Allele origin: unknown	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center Accession: SCV004013446.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023
Pathogenic (Jun 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226903.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: PM1, PS3, PS4 Number of individuals with the variant: 2
Pathogenic (Oct 16, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024334.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Nov 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847543.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (Jan 11, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002723049.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 11464238‚ 25393764‚ 9288758 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198751.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Apr 01, 1999)	no assertion criteria provided Method: literature only	FAMILIAL MEDITERRANEAN FEVER Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022808.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 15, 2020	Publications: PubMed (3) PubMed: 9288758‚ 9288094‚ 10090880 Comment on evidence: In the affected offspring of a single Armenian family with familial Mediterranean fever (FMF; 249100), the International FMF Consortium (1997) found homozygosity for a 2040G-C … (more) In the affected offspring of a single Armenian family with familial Mediterranean fever (FMF; 249100), the International FMF Consortium (1997) found homozygosity for a 2040G-C transversion that resulted in a met680-to-ile (M680I) amino acid substitution in the pyrin protein. In Turkish and Armenian FMF patients with the ARM2 haplotype, the French FMF Consortium (1997) likewise found this G-C transversion at nucleotide 1130 of their partial cDNA sequence of the MEFV gene. Aksentijevich et al. (1999) found that the same amino acid change was produced by a 2040G-A transition; see 608107.0013. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930242.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (Mar 06, 2024)	no assertion criteria provided Method: clinical testing	MEFV-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005347588.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (Mar 15, 2019)	no assertion criteria provided Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV001132428.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019	Publications: PubMed (8) PubMed: 9288758‚ 15951859‚ 10090880‚ 19863562‚ 16785446‚ 11468188‚ 12401847‚ 23907647
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462099.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807652.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741393.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959280.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973052.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (May 01, 2022)	no assertion criteria provided Method: clinical testing	Familial Mediterranean fever Affected status: yes Allele origin: germline	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska" Accession: SCV002573424.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022
Pathogenic (Nov 02, 2023)	no assertion criteria provided Method: clinical testing	Familial Mediterranean fever Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004101055.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023
not provided (-)	no classification provided Method: literature only	Familial Mediterranean fever Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000484965.2 First in ClinVar: Jun 28, 2015 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 16627024 BookShelf: NBK1227 BookShelf: NBK1227
Pathogenic (Oct 04, 2020)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV001448269 appears to (...more) Source: NCBI	Familial Mediterranean fever, autosomal dominant Familial Mediterranean fever Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001448269.1 First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020	Sex: female
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Comment:

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.

Comment:

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)

Comment:

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.

Comment:

The MEFV c.2040G>C; p.Met680Ile variant (rs28940580) has been published as a common familial Mediterranean fever pathogenic variant (Moradian 2014, The International FMF Consortium 1997). This variant is also reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 36507). It is found in the general population with an overall allele frequency of 0.01% (26/251474 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Moradian MM et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 2014; 16(3):258-63. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997; 90:797-807.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
MEFV mutations in Iranian Azari Turkish patients with Henoch-Schönlein purpura.	Bonyadi M	Turkish journal of medical sciences	2016	PMID: 27513391
Familial Mediterranean Fever.	Adam MP	-	2016	PMID: 20301405
[Influence of M680I and M694V mutations on pyrin's domain B30.2 tertiary structure and it's complex formation ability with caspase-1].	Arakelov GG	Molekuliarnaia biologiia	2015	PMID: 26510601
Familial Mediterranean fever associated with MEFV mutations in a large cohort of Cypriot patients.	Neocleous V	Annals of human genetics	2015	PMID: 25393764
Patient management and the association of less common familial Mediterranean fever symptoms with other disorders.	Moradian MM	Genetics in medicine : official journal of the American College of Medical Genetics	2014	PMID: 23907647
Common MEFV gene mutations in Turkish patients with Behcet's disease.	Tasliyurt T	Gene	2013	PMID: 23973724
Common MEFV mutations in Iranian Azeri Turkish patients with Behçet's disease.	Esmaeili M	Scandinavian journal of rheumatology	2011	PMID: 21623663
Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice.	Chae JJ	Immunity	2011	PMID: 21600797
Association of familial Mediterranean fever-related MEFV variations with ankylosing spondylitis.	Cosan F	Arthritis and rheumatism	2010	PMID: 20669279
1Novel MEFV transcripts in Familial Mediterranean fever patients and controls.	Medlej-Hashim M	BMC medical genetics	2010	PMID: 20534143
Evaluation of common mutations in the Mediterranean fever gene in Multiple Sclerosis patients: is it a susceptibility gene?	Unal A	Journal of the neurological sciences	2010	PMID: 20483145
High frequency of MEFV gene mutations in patients with myeloid neoplasm.	Oktenli C	International journal of hematology	2010	PMID: 20437121
A case of familial Mediterranean fever associated with compound heterozygosity for the pyrin variant L110P-E148Q/M680I in Japan.	Oshima K	Modern rheumatology	2010	PMID: 19967574
MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever.	Bonyadi M	Clinical genetics	2009	PMID: 19863562
Familial Mediterranean fever with chronic ascites: a case report and a review of literature.	Ureten K	Rheumatology international	2009	PMID: 19151977
MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever.	Giaglis S	Clinical genetics	2007	PMID: 17489852
The fate of 12 recessive mutations in a single village.	Zlotogora J	Annals of human genetics	2007	PMID: 17331080
The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production.	Chae JJ	Proceedings of the National Academy of Sciences of the United States of America	2006	PMID: 16785446
Familial Mediterranean fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype-genotype correlation.	Mattit H	European journal of medical genetics	2006	PMID: 16627024
Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever.	Belmahi L	Comptes rendus biologies	2006	PMID: 16439335
Regular abdominal pain and fever in each menstruation onset: an unusual menses-associated familial Mediterrenean fever attacks and a favor result on colchicine treatment.	Düzgün N	Rheumatology international	2006	PMID: 16179998
MEFV analysis is of particularly weak diagnostic value for recurrent fevers in Western European Caucasian patients.	Tchernitchko D	Arthritis and rheumatism	2005	PMID: 16255051
Genetic screening of familial Mediterranean fever mutations in the Palestinian population.	Ayesh SK	Saudi medical journal	2005	PMID: 15951859
MEFV mutations in familial Mediterranean fever: association of M694V homozygosity with arthritis.	Olgun A	Rheumatology international	2005	PMID: 14727057
Familial Mediterranean fever, inflammation and nephrotic syndrome: fibrillary glomerulopathy and the M680I missense mutation.	Fisher PW	BMC nephrology	2003	PMID: 12908875
The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever.	Gershoni-Baruch R	Arthritis and rheumatism	2003	PMID: 12687559
MEFV gene mutations in familial Mediterranean fever phenotype II patients with renal amyloidosis in childhood: a retrospective clinicopathological and molecular study.	Balci B	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2002	PMID: 12401847
Mutational spectrum in the MEFV and TNFRSF1A genes in patients suffering from AA amyloidosis and recurrent inflammatory attacks.	Dodé C	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2002	PMID: 12105243
The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever.	Gershoni-Baruch R	European journal of human genetics : EJHG	2002	PMID: 11938447
The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments.	Mansfield E	Blood	2001	PMID: 11468188
The spectrum of Familial Mediterranean Fever (FMF) mutations.	Touitou I	European journal of human genetics : EJHG	2001	PMID: 11464238
Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever.	Cazeneuve C	American journal of human genetics	2000	PMID: 11017802
MEFV mutations in multiplex families with familial Mediterranean fever: is a particular genotype necessary for amyloidosis?	Tekin M	Clinical genetics	2000	PMID: 10905662
The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant?	Ben-Chetrit E	Human mutation	2000	PMID: 10737995
MEFV mutations in Turkish patients suffering from Familial Mediterranean Fever.	Akar N	Human mutation	2000	PMID: 10612841
Direct detection of common mutations in the familial Mediterranean fever gene (MEFV) using naturally occurring and primer mediated restriction fragment analysis. Mutation in brief no. 257. Online.	Gershoni-Baruch R	Human mutation	1999	PMID: 10447272
MEFV-Gene analysis in armenian patients with Familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications.	Cazeneuve C	American journal of human genetics	1999	PMID: 10364520
Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.	Aksentijevich I	American journal of human genetics	1999	PMID: 10090880
Pyrin/marenostrin mutations in familial Mediterranean fever.	Booth DR	QJM : monthly journal of the Association of Physicians	1998	PMID: 10024914
Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium.	-	Cell	1997	PMID: 9288758
A candidate gene for familial Mediterranean fever.	French FMF Consortium	Nature genetics	1997	PMID: 9288094
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MEFV	-	-	-	-
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Text-mined citations for rs28940580 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28940580 ...