VCV000002538.115 - ClinVar

NM_000243.3(MEFV):c.2080A>G (p.Met694Val)

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.

(53)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Genotype

NM_000243.3(MEFV):c.[2080A>G];[2177T>C]

Identifiers

NM_000243.3(MEFV):c.2080A>G (p.Met694Val)

Variation ID: 2538 Accession: VCV000002538.115

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 3243407 (GRCh38) [ NCBI UCSC ] 16: 3293407 (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.2080A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000234.1:p.Met694Val	missense
NM_001198536.2:c.*284A>G		3 prime UTR
NC_000016.10:g.3243407T>C
NC_000016.9:g.3293407T>C
NG_007871.1:g.18221A>G
LRG_190:g.18221A>G
LRG_190t1:c.2080A>G	LRG_190p1:p.Met694Val
	O15553:p.Met694Val

... more HGVS ... less HGVS

Protein change

Other names

M694V
NM_000243.2(MEFV):c.2080A>G(p.Met694Val)

Canonical SPDI

NC_000016.10:3243406:T:C

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.

0.00020 (C)

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

The Genome Aggregation Database (gnomAD) 0.00012

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00022

Exome Aggregation Consortium (ExAC) 0.00023

The Genome Aggregation Database (gnomAD), exomes 0.00028

Links

ClinGen: CA280091 UniProtKB: O15553#VAR_009062 OMIM: 608107.0001 dbSNP: rs61752717 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	956	1257
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/Likely pathogenic (16)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000002647.45
Familial Mediterranean fever Familial Mediterranean fever, autosomal dominant	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 3, 2021	RCV000763381.14
Abnormal facial shape Abnormal nonverbal communicative behavior Autistic behavior Brachydactyly Generalized hypotonia Microcephaly Profound global developmental delay Stereotypic movement disorder Synophrys	Pathogenic (1)	criteria provided, single submitter	-	RCV000735306.10
Familial Mediterranean fever, autosomal dominant	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jul 20, 2024	RCV001028046.20
Acute febrile neutrophilic dermatosis Familial Mediterranean fever Familial Mediterranean fever, autosomal dominant	Pathogenic (1)	criteria provided, single submitter	Jun 30, 2021	RCV001535935.11
not provided	Pathogenic (16)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000216751.65
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Feb 6, 2018	RCV002415387.9
Autoinflammatory syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 19, 2022	RCV002262539.10
Recurrent fever	Pathogenic (1)	criteria provided, single submitter	Sep 6, 2023	RCV003325449.6
MEFV-related disorder	Pathogenic (2)	criteria provided, single submitter	-	RCV003335011.2
Abnormal anterior fontanelle morphology Abnormal cerebral white matter morphology Central hypotonia Cryptorchidism Deep plantar creases Global developmental delay Macrocephaly Seizure	Pathogenic (1)	criteria provided, single submitter	-	RCV000735284.10
Acute febrile neutrophilic dermatosis	Pathogenic (1)	criteria provided, single submitter	Feb 25, 2020	RCV001197704.10
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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 (Nov 24, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281543.1 First in ClinVar: May 29, 2016 Last updated: May 29, 2016
Pathogenic (Aug 19, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331542.4 First in ClinVar: Dec 06, 2016 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: 2 Sex: mixed
Pathogenic (Oct 18, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193946.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (5) PubMed: 10364520‚ 11464248‚ 23907647‚ 23334425‚ 16785446 Comment: NM_000243.2(MEFV):c.2080A>G(M694V, aka MED) is classified as pathogenic in the context of familial Mediterranean fever. In the absence of a known personal and/or family history of … (more) NM_000243.2(MEFV):c.2080A>G(M694V, aka MED) is classified as pathogenic in the context of familial Mediterranean fever. In the absence of a known personal and/or family history of inflammatory disease, the clinical significance of MEFV variant status is uncertain. Sources cited for classification include the following: PMID 10364520, 11464248, 23907647, 23334425, 16785446. Classification of NM_000243.2(MEFV):c.2080A>G(M694V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Jun 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever Affected status: yes Allele origin: germline	Hadassah Hebrew University Medical Center Accession: SCV001437667.1 First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020	Publications: PubMed (1) PubMed: 33223529
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: SCV001447043.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Unexplained fevers (present) , Abnormal inflammatory response (present) , Pain (present) Sex: female
Pathogenic (Oct 04, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	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: SCV001448264.1 First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020	Sex: male
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: SCV001368483.2 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,PS3,PS4_Supp,PM1,PM3.
Pathogenic (Jun 30, 2021)	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: SCV001752593.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 Comment: This variant has been detected in individual(s) who were sent for testing of Renasight - kidney gene panel.
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: SCV001810497.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Sex: mixed
Pathogenic (May 27, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139826.2 First in ClinVar: Jan 09, 2020 Last updated: Jun 05, 2022
Pathogenic (Apr 19, 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: SCV002543732.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Pathogenic (Jun 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026421.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PS4, PS3, PM3
Pathogenic (Sep 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Recurrent fever Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV004032056.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023
Pathogenic (Jan 03, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017261.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Nov 22, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604181.10 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: The MEFV c.2080A>G;p.Met694Val variant (rs61752717) has been published as a common familial Mediterranean fever (FMF) pathogenic variant (The International FMF Consortium 1997, Touitou 2001). Functional … (more) The MEFV c.2080A>G;p.Met694Val variant (rs61752717) has been published as a common familial Mediterranean fever (FMF) pathogenic variant (The International FMF Consortium 1997, Touitou 2001). Functional analysis of the variant protein shows diminished capacity to suppress IL-8 secretion in synovial cell cultures (Sugiyama 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2538), and is seen in the general population at an overall frequency of 0.03% (77/282876 including 1 homozygote) in the Genome Aggregation Database. Additionally, another variant at this codon (Met694Ile) has been reported in individuals with FMF and is considered pathogenic (Sugiyama 2014). Based on the above information, this variant is considered pathogenic. References: The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. 1997 Cell. 90:797-807. PMID: 9288758. Sugiyama R et al. Defect of suppression of inflammasome-independent interleukin-8 secretion from SW982 synovial sarcoma cells by familial Mediterranean fever-derived pyrin mutations. Mol Biol Rep. 2014 Jan;41(1):545-53. PMID: 24318677. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001 9(7):478-483. PMID: 11464238. (less)
Pathogenic (Jun 23, 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: SCV004847545.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Met694Val variant in MEFV is the most common cause of familial Mediterranean fever (FMF) in Israel, Armenia and Turkey, and it is also present … (more) The p.Met694Val variant in MEFV is the most common cause of familial Mediterranean fever (FMF) in Israel, Armenia and Turkey, and it is also present in other populations (Dewalle 1998 PMID: 9781020, Cazeneuve 1999 PMID: 10364520, Bathelier 2010 PMID: 21290976, Akpolat 2012 PMID: 22037353). In the homozygous state this variant is associated with a higher rate of amyloidosis and a lower response to colchicine (Soylemezoglu 2010 PMID: 20008920, Akpolat 2012 PMID: 22037353). It has also been reported in ClinVar (Variation ID 2385). It has been identified in 12/68010 European chromosomes by gnomAD. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, in vitro functional studies show decreased capacity of the variant protein to suppress IL-8 secretion in synovial cell cultures and FMF-knock-in mice studies showed decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo, thereby providing some evidence that this variant impacts protein function (Sugiyama 2014 PMID: 24318677, Park 2016 PMID: 27270401). Additionally, another variant involving this codon (p.Met694Ile) has been reported in individuals with FMF and is classified as pathogenic by several clinical laboratories in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive FMF. ACMG/AMP Criteria applied: PS3_Moderate, PM3_VeryStrong, PM2_Supporting, PP1_strong. (less)
Pathogenic (Feb 06, 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: SCV002726824.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 11938447‚ 24369413‚ 9288758 Comment: The p.M694V pathogenic mutation (also known as c.2080A>G), located in coding exon 10 of the MEFV gene, results from an A to G substitution at … (more) The p.M694V pathogenic mutation (also known as c.2080A>G), located in coding exon 10 of the MEFV gene, results from an A to G substitution at nucleotide position 2080. The methionine at codon 694 is replaced by valine, an amino acid with highly similar properties. This is one of the most common mutations in individuals with familial Mediterranean fever (FMF), particularly among individuals of North African Jewish descent. In addition, homozygosity of the p.M694V mutation is associated with a severe phenotype and 6-fold higher risk of amyloidosis compared with other genotypes (The International FMF Consortium. Cell, 1997 Aug;90:797-807; Gershoni-Baruch R et al. Eur. J. Hum. Genet., 2002 Feb;10:145-9; Kasifoglu T et al. Rheumatology (Oxford), 2014 Apr;53:741-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Mar 30, 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: SCV001524568.2 First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024
Likely pathogenic (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Familial Mediterranean fever Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803512.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018	Publications: PubMed (1) PubMed: 24318677 Comment: This variant is interpreted as a Likely Pathogenic, for Familial mediterranean fever, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM1 => Located … (more) This variant is interpreted as a Likely Pathogenic, for Familial mediterranean fever, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PS3 => Well-established functional studies show a deleterious effect (PMID:24318677). PM2 => Present in Exome Aggregation Consortium with allele frequency compatible with disease prevalence. According to Genetics Home Reference (https://ghr.nlm.nih.gov/condition/familial-mediterranean-fever), Familial Mediterranean fever primarily affects populations originating in the Mediterranean region, particularly people of Armenian, Arab, Turkish, or Jewish ancestry. The disorder affects 1 in 200 to 1,000 people in these populations. It is less common in other populations. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormal anterior fontanelle morphology Abnormal cerebral white matter morphology Central hypotonia Cryptorchidism Deep plantar creases Global developmental delay Macrocephaly Seizure Affected status: yes Allele origin: germline	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV000854437.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Sex: male Ethnicity/Population group: Non-Hispanic, White
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormal facial shape Autistic behavior Brachydactyly Generalized hypotonia Abnormal nonverbal communicative behavior Microcephaly Profound global developmental delay Motor stereotypies Synophrys Affected status: yes Allele origin: germline	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV000854459.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Sex: male
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Familial Mediterranean fever Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894080.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely pathogenic (May 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV001251817.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Pathogenic (Dec 09, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429245.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Number of individuals with the variant: 1
Pathogenic (Jul 28, 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: SCV001450237.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 91
Pathogenic (Jul 15, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279058.9 First in ClinVar: May 29, 2016 Last updated: Apr 17, 2019	Comment: Reported as the most common pathogenic variant associated with familial Mediterranean fever, especially in Turkish, Armenian, Arab, and Jewish populations (Ozen, 2017; Askentijevich et al., … (more) Reported as the most common pathogenic variant associated with familial Mediterranean fever, especially in Turkish, Armenian, Arab, and Jewish populations (Ozen, 2017; Askentijevich et al., 1999); Individuals who are homozygous for M694V are at higher risk for earlier onset, more severe symptoms, and for developing amyloidosis (Ozen, 2017); Multiple published functional and FMF-knock-in mice studies demonstrated the damaging effect of the M694V variant, e.g., showing loss of suppression of IL-8 secretion in vitro (Sugiyama et al., 2014) and decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo (Park, 2016); Other missense variants altering the same residue (M694I/K/L) and nearby residues (e.g., K695R/M) have been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 21557533, 27538774, 27270401, 28800602, 28828621, 24369413, 11728994, 20669279, 11005788, 21483284, 23832993, 21995303, 21360101, 21329287, 22960328, 23588594, 22037353, 22975760, 24123366, 20437121, 25036284, 22790142, 20008920, 20483145, 22532615, 11470495, 10667038, 22487161, 23633568, 22783597, 19151978, 21259007, 23334425, 20049453, 20828792, 10879615, 21623663, 21228398, 10090880, 24251727, 23907647, 24533546, 26400644, 24318677, 9288758, 27994174, 27766107, 27621632, 27659338, 14636645, 15711787, 25550179, 12189462, 26071026, 26510601, 16721494, 18183427, 26360812, 18318646, 16179998, 17111701, 28573371, 11781702, 19151977, 28386255, 16523434, 17949559, 18408398, 9781020, 11175300, 14615741, 30826945, 30946743, 29543225, 30009667, 31814694, 30783801, 29027576, 30171907, 32199921, 32601469, 31589614, 33440462, 11977178, 30755392, 32888943, 29080837, 10852276, 10662876) (less)
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: SCV000052840.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022	Publications: PubMed (1) PubMed: 19790133 Comment: Converted during submission to Pathogenic. Observation 1: Number of individuals with the variant: 10 Observation 2: Tissue: Blood Observation 3: Tissue: Blood Observation 4: Tissue: Blood Observation 5: Tissue: Blood
Pathogenic (May 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Familial Mediterranean fever Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV002495841.1 First in ClinVar: Apr 11, 2022 Last updated: Apr 11, 2022	Comment: MEFV NM_000243.2 exon 10 p.Met694Val (c.2080A>G): This variant is one of the most common pathogenic variants for Familial Mediterranean Fever (FMF). This variant has been … (more) MEFV NM_000243.2 exon 10 p.Met694Val (c.2080A>G): This variant is one of the most common pathogenic variants for Familial Mediterranean Fever (FMF). This variant has been reported in several publications in individuals with FMF in the homozygous, heterozygous and compound heterozygous state, including a Genereviews entry describing this variant as disease causing (Selected Publications: International FMF Consortium 1997 PMID:8288758, Barut 2018 PMID:28828621, Kriegshauser 2018 PMID:29543225). This variant is present in 0.01% (12/68010) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3243407-T-C?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:2538). In summary, this variant is classified as pathogenic based on the data above. (less)
Pathogenic (Aug 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580916.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PS4, PM1, PM3, PM5, PP1	Number of individuals with the variant: 14 Sex: female
Pathogenic (May 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV002758595.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: ACMG criteria used to clasify this variant: PP1, PS3, PM1, PS4, PM5
Pathogenic (Feb 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807537.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PM3 very strong, PM5 moderated, PP1 strong Number of individuals with the variant: 1 Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever Affected status: yes Allele origin: unknown	3billion Accession: SCV003841560.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (4) PubMed: 21600797‚ 10879615‚ 9288758‚ 11977178 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.027%). Functional studies provide strong evidence of the … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.027%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21600797). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.41; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002538). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 10879615, 9288758). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 11977178). A different missense change at the same codon (p.Met694Ile) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002539). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Fever (present) , Diarrhea (present) , Arthralgia (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MEFV-related disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046213.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This variant is a common cause of familial Mediterranean fever (FMF), and has been previously reported as a heterozygous, compound heterozygous, and homozygous change in … (more) This variant is a common cause of familial Mediterranean fever (FMF), and has been previously reported as a heterozygous, compound heterozygous, and homozygous change in patients with MEFV-related disorders (PMID: 9288758, 20301405). Functional studies have shown that this missense change has a damaging effect on the function of the MEFV protein (PMID: 24318677). It is present in the gnomAD population database at a frequency of 0.027% (77/282876) and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.2080A>G (p.Met694Val) variant is classified as Pathogenic. (less)
Pathogenic (Sep 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002072563.2 First in ClinVar: Feb 05, 2022 Last updated: Nov 04, 2023	Comment: Criteria applied: PS3,PS4,PM5 Clinical Features: Hypotonia (present) , Cerebral palsy (present) , Infantile muscular hypotonia (present) , Microcephaly (present) , Mild microcephaly (present) , Cognitive impairment (present) , Global developmental … (more) Hypotonia (present) , Cerebral palsy (present) , Infantile muscular hypotonia (present) , Microcephaly (present) , Mild microcephaly (present) , Cognitive impairment (present) , Global developmental delay (present) , Hip dislocation (present) , Intellectual disability (present) (less) Sex: female
Pathogenic (Sep 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: SCV001712843.3 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Comment: PP5, PM1, PS3, PS4_moderate Number of individuals with the variant: 13
Pathogenic (Jan 29, 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: SCV000629034.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (9) PubMed: 28492532‚ 9781020‚ 10364520‚ 20008920‚ 21290976‚ 22037353‚ 24318677‚ 10787449‚ 15942916 Comment: This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 694 of the MEFV protein (p.Met694Val). … (more) This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 694 of the MEFV protein (p.Met694Val). This variant is present in population databases (rs61752717, gnomAD 0.04%). This missense change has been observed in individual(s) with familial Mediterranean fever (FMF) and in the homozygous state this variant is associated with a higher rate of amyloidosis and a lower response to colchicine (PMID: 9781020, 10364520, 20008920, 21290976, 22037353). 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: 2538). 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. Experimental studies have shown that this missense change affects MEFV function (PMID: 24318677). This variant disrupts the p.Met694 amino acid residue in MEFV. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10787449, 15942916, 24318677). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Familial Mediterranean fever Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051859.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005060943.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Comment: The observed missense variant c.2080A>G (p.Met694Val) in MEFV gene has been reported previously in multiple individuals in both homozygous and compound heterozygous state in individuals … (more) The observed missense variant c.2080A>G (p.Met694Val) in MEFV gene has been reported previously in multiple individuals in both homozygous and compound heterozygous state in individuals affected with familial mediterranean fever (Grossman et al. 2018). Functional studies of this variant have shown impaired pyrin (encoded by the MEFV gene) function (Sugiyama et al. 2014). Exon 10 is a hotspot region for variants in MEFV gene causing familial mediterranean fever (Grossman et al. 2018). The p.Met694Val variant is present with an allele frequency of 0.03% (71 heterozygotes; 1 homozygote) in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Met694Val in MEFV is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 694 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: unknown Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005093845.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Comment: ACMG Criteria: PS3, PS4, PM1, PM3, PM5, PP5; Variant was found in heterozygous state
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: SCV001245670.24 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: MEFV: PP1:Strong, PM1, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, BP4 Number of individuals with the variant: 251
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Familial Mediterranean fever Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462098.1 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: SCV001807357.1 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: SCV001744126.3 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: SCV001952766.1 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: SCV001973494.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Jan 01, 2010)	no assertion criteria provided Method: literature only	FAMILIAL MEDITERRANEAN FEVER Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022805.6 First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022	Publications: PubMed (8) PubMed: 9288758‚ 9288094‚ 9781020‚ 10364520‚ 11464248‚ 21290976‚ 27030597‚ 30171907 Comment on evidence: In a large number of individuals affected with familial Mediterranean fever (FMF; 249100), the International FMF Consortium (1997) identified a 2080A-G transition in the pyrin … (more) In a large number of individuals affected with familial Mediterranean fever (FMF; 249100), the International FMF Consortium (1997) identified a 2080A-G transition in the pyrin gene, resulting in a met694-to-val (M694V) substitution. The affected individuals had 4 apparently distinct haplotypes. The French FMF Consortium (1997) identified this A-G transition in the MEFV gene at nucleotide 1170 of their partial cDNA sequence. They referred to the mutation as the 'MED' variation because it was observed in affected members of families of various origins (Jewish, Armenian, Turkish, Arabian) sharing the MED haplotype. The ethnic diversity indicated that the mutation is ancient and confirms founder effect in the origin of a large fraction of FMF cases in the Mediterranean basin. The MED mutation is found in about 80% of the FMF Jewish (Iraqi and North African) chromosomes. To see if the presence of this mutation could be correlated with particular traits of the disease, Dewalle et al. (1998) examined clinical features in a panel of 109 Jewish FMF patients with 0, 1, or 2 MED mutations. They showed that homozygosity for this mutation was significantly associated with a more severe form of the disease. In homozygous patients, the disease started earlier (mean age 6.4 vs 13.6) and both arthritis and pleuritis were twice as frequent as in patients with one or no M694V mutation. Moreover, all 3 of 3 patients with amyloidosis displayed 2 MED mutations. No association was found with fever, peritonitis, response to colchicine, and erysipeloid eruption. Cazeneuve et al. (1999) found that the M694V allele had a frequency of 44.8% among 90 Armenian FMF patients from 77 unrelated families. They also found that the homozygous M694V genotype was associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes. Yilmaz et al. (2001) found that the M694V allele had a frequency of 51.6% among 450 Turkish FMF patients. The carrier frequency in a Turkish population sample of 100 was 3%. Bathelier et al. (2010) identified the M694V allele in 36 (6%) of 604 French patients with FMF: 7 patients were homozygous for the mutation and 29 were heterozygous. Heterozygosity for the M694V allele was found in 3 of 779 controls, which was significantly lower than among patients. Five of the 604 FMF patients had amyloidosis, and 2 of the patients with amyloidosis were homozygous for the M694V allele. Bathelier et al. (2010) concluded that M694V is a risk allele for the development of amyloidosis in FMF. Among patients carrying the mutant allele, 47% were of North African Jewish ancestry. In addition, the 3 controls who were heterozygous for the mutation were of Sephardic origin. In a Lebanese female with autosomal recessive FMF, Masters et al. (2016) identified compound heterozygous missense mutations in the FMF gene: M694V and S242R (608107.0021). Each mutation was inherited from a parent: the unaffected mother carried the S242R variant in heterozygous state, suggesting incomplete penetrance of acute febrile neutrophilic dermatosis (AFND; 608068). The patient had periodic fevers, serositis, recurrent aphthous ulcers reminiscent of Behcet disease (BD; 109650), transient skin rashes/nodules, and joint pain that was partially controlled by colchicine. Grossman et al. (2019) compared 57 patients with FMF who were homozygous for the M694V mutation to a cohort of 56 patients with FMF and other MEFV genotypes. They found that the M694V homozygotes had more severe disease, including more attacks per year, higher colchicine dosing, and lower colchicine response compared to the cohort of other genotypes. (less)
Pathogenic (Oct 09, 2023)	no assertion criteria provided Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004041643.1 First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023
Pathogenic (Feb 05, 2020)	no assertion criteria provided Method: clinical testing	Familial Mediterranean fever, autosomal dominant Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001190817.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001550173.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The MEFV p.Met694Val variant is the most common variant associated with Familial Mediterranean fever (FMF), and has been identified in 1598 of 3112 proband chromosomes … (more) The MEFV p.Met694Val variant is the most common variant associated with Familial Mediterranean fever (FMF), and has been identified in 1598 of 3112 proband chromosomes (frequency: 0.513) from patients with FMF (Yilmaz_2001_PMID:11464248; Tunca_2005_PMID:15643295; Domingo_2000_PMID:10854105). The variant was also identified in dbSNP (ID: rs61752717), ClinVar (classified as pathogenic by Invitae, GeneDx and nine other laboratories, and as likely pathogenic by the Swiss Institute of Bioinformatics) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 77 of 282876 chromosomes (1 homozygous) at a frequency of 0.000272 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 7 of 7226 chromosomes (freq: 0.000969), European (non-Finnish) in 59 of 129184 chromosomes (freq: 0.000457), Latino in 9 of 35438 chromosomes (freq: 0.000254) and African in 2 of 24968 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. One study of a Turkish population with FMF found that homozygosity for the M694V variant was associated with an earlier age of onset and a higher likelihood or developing arthritis and arthralgia (Tunca_2005_PMID:15643295). Individuals with the p.M694V pathogenic variant, particularly homozygous individuals, are at increased risk for amyloidosis (Dusunsel_2008_PMID:18353061) and have a decreased response to colchicine (Soylemezoglu_2010_PMID:20008920). Another study found that the M694V variant was associated with increased susceptibility to ankylosing spondylitis (OR=3.33) (Zhong_2017_PMID:28800602). The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (MaxEntScan, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity.The p.Met694 residue is not conserved in mammals and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Further, functional studies of the M694V variant have shown impaired pyrin (encoded by the MEFV gene) function (Sugiyama_2014_PMID:24318677). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (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: SCV001929715.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (Aug 05, 2024)	no assertion criteria provided Method: clinical testing	MEFV-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005356687.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MEFV c.2080A>G variant is predicted to result in the amino acid substitution p.Met694Val. This variant is one of the most common pathogenic variants identified … (more) The MEFV c.2080A>G variant is predicted to result in the amino acid substitution p.Met694Val. This variant is one of the most common pathogenic variants identified in patients with familial Mediterranean fever (FMF; Moradian et al. 2013. PubMed ID: 23907647; Comak et al. 2013. PubMed ID: 23588594; Sedivá et al. 2014. PubMed ID: 24251727). This variant has been identified in patients in the homozygous and compound heterozygous states, as well as in heterozygous carriers with clinical manifestations of FMF (Moradian et al. 2013. PubMed ID: 23907647; Sedivá et al. 2014. PubMed ID: 24251727). This variant is reported in 0.046% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
not provided (-)	no classification provided Method: phenotyping only	Familial Mediterranean fever Affected status: yes Allele origin: maternal	GenomeConnect, ClinGen Accession: SCV001423313.1 First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020	Comment: Variant interpretted as Pathogenic and reported on 06-02-2016 by Lab or GTR ID 506013. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpretted as Pathogenic and reported on 06-02-2016 by Lab or GTR ID 506013. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Failure to thrive (present) , Abnormality of the skull (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , EEG abnormality (present) … (more) Failure to thrive (present) , Abnormality of the skull (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , EEG abnormality (present) , Encephalopathy (present) , Generalized hypotonia (present) , Movement disorder (present) , Seizures (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormality of the musculature of the pelvis (present) , Abnormal pattern of respiration (present) , Feeding difficulties (present) , Abnormality of esophagus morphology (present) , Abnormality of the stomach (present) , Abnormality of the male genitalia (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: male Method: Sanger Sequencing Testing laboratory: Children's Hospital of Los Angeles, Center for Personalized Medicine Date variant was reported to submitter: 2016-06-02 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	Familial Mediterranean fever Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000484968.2 First in ClinVar: Dec 06, 2016 Last updated: Oct 01, 2022	Publications: PubMed (4) PubMed: 16889173‚ 15643295‚ 18353061‚ 20008920 BookShelf: NBK1227 BookShelf: NBK1227 Geographic origin: Mediterranean region
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Comment:

NM_000243.2(MEFV):c.2080A>G(M694V, aka MED) is classified as pathogenic in the context of familial Mediterranean fever. In the absence of a known personal and/or family history of inflammatory disease, the clinical significance of MEFV variant status is uncertain. Sources cited for classification include the following: PMID 10364520, 11464248, 23907647, 23334425, 16785446. Classification of NM_000243.2(MEFV):c.2080A>G(M694V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

The MEFV c.2080A>G;p.Met694Val variant (rs61752717) has been published as a common familial Mediterranean fever (FMF) pathogenic variant (The International FMF Consortium 1997, Touitou 2001). Functional analysis of the variant protein shows diminished capacity to suppress IL-8 secretion in synovial cell cultures (Sugiyama 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2538), and is seen in the general population at an overall frequency of 0.03% (77/282876 including 1 homozygote) in the Genome Aggregation Database. Additionally, another variant at this codon (Met694Ile) has been reported in individuals with FMF and is considered pathogenic (Sugiyama 2014). Based on the above information, this variant is considered pathogenic. References: The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. 1997 Cell. 90:797-807. PMID: 9288758. Sugiyama R et al. Defect of suppression of inflammasome-independent interleukin-8 secretion from SW982 synovial sarcoma cells by familial Mediterranean fever-derived pyrin mutations. Mol Biol Rep. 2014 Jan;41(1):545-53. PMID: 24318677. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001 9(7):478-483. PMID: 11464238.

Comment:

The p.Met694Val variant in MEFV is the most common cause of familial Mediterranean fever (FMF) in Israel, Armenia and Turkey, and it is also present in other populations (Dewalle 1998 PMID: 9781020, Cazeneuve 1999 PMID: 10364520, Bathelier 2010 PMID: 21290976, Akpolat 2012 PMID: 22037353). In the homozygous state this variant is associated with a higher rate of amyloidosis and a lower response to colchicine (Soylemezoglu 2010 PMID: 20008920, Akpolat 2012 PMID: 22037353). It has also been reported in ClinVar (Variation ID 2385). It has been identified in 12/68010 European chromosomes by gnomAD. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, in vitro functional studies show decreased capacity of the variant protein to suppress IL-8 secretion in synovial cell cultures and FMF-knock-in mice studies showed decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo, thereby providing some evidence that this variant impacts protein function (Sugiyama 2014 PMID: 24318677, Park 2016 PMID: 27270401). Additionally, another variant involving this codon (p.Met694Ile) has been reported in individuals with FMF and is classified as pathogenic by several clinical laboratories in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive FMF. ACMG/AMP Criteria applied: PS3_Moderate, PM3_VeryStrong, PM2_Supporting, PP1_strong.

Comment:

The p.M694V pathogenic mutation (also known as c.2080A>G), located in coding exon 10 of the MEFV gene, results from an A to G substitution at nucleotide position 2080. The methionine at codon 694 is replaced by valine, an amino acid with highly similar properties. This is one of the most common mutations in individuals with familial Mediterranean fever (FMF), particularly among individuals of North African Jewish descent. In addition, homozygosity of the p.M694V mutation is associated with a severe phenotype and 6-fold higher risk of amyloidosis compared with other genotypes (The International FMF Consortium. Cell, 1997 Aug;90:797-807; Gershoni-Baruch R et al. Eur. J. Hum. Genet., 2002 Feb;10:145-9; Kasifoglu T et al. Rheumatology (Oxford), 2014 Apr;53:741-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

This variant is interpreted as a Likely Pathogenic, for Familial mediterranean fever, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PS3 => Well-established functional studies show a deleterious effect (PMID:24318677). PM2 => Present in Exome Aggregation Consortium with allele frequency compatible with disease prevalence. According to Genetics Home Reference (https://ghr.nlm.nih.gov/condition/familial-mediterranean-fever), Familial Mediterranean fever primarily affects populations originating in the Mediterranean region, particularly people of Armenian, Arab, Turkish, or Jewish ancestry. The disorder affects 1 in 200 to 1,000 people in these populations. It is less common in other populations.

Comment:

Reported as the most common pathogenic variant associated with familial Mediterranean fever, especially in Turkish, Armenian, Arab, and Jewish populations (Ozen, 2017; Askentijevich et al., 1999); Individuals who are homozygous for M694V are at higher risk for earlier onset, more severe symptoms, and for developing amyloidosis (Ozen, 2017); Multiple published functional and FMF-knock-in mice studies demonstrated the damaging effect of the M694V variant, e.g., showing loss of suppression of IL-8 secretion in vitro (Sugiyama et al., 2014) and decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo (Park, 2016); Other missense variants altering the same residue (M694I/K/L) and nearby residues (e.g., K695R/M) have been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 21557533, 27538774, 27270401, 28800602, 28828621, 24369413, 11728994, 20669279, 11005788, 21483284, 23832993, 21995303, 21360101, 21329287, 22960328, 23588594, 22037353, 22975760, 24123366, 20437121, 25036284, 22790142, 20008920, 20483145, 22532615, 11470495, 10667038, 22487161, 23633568, 22783597, 19151978, 21259007, 23334425, 20049453, 20828792, 10879615, 21623663, 21228398, 10090880, 24251727, 23907647, 24533546, 26400644, 24318677, 9288758, 27994174, 27766107, 27621632, 27659338, 14636645, 15711787, 25550179, 12189462, 26071026, 26510601, 16721494, 18183427, 26360812, 18318646, 16179998, 17111701, 28573371, 11781702, 19151977, 28386255, 16523434, 17949559, 18408398, 9781020, 11175300, 14615741, 30826945, 30946743, 29543225, 30009667, 31814694, 30783801, 29027576, 30171907, 32199921, 32601469, 31589614, 33440462, 11977178, 30755392, 32888943, 29080837, 10852276, 10662876)

Comment:

MEFV NM_000243.2 exon 10 p.Met694Val (c.2080A>G): This variant is one of the most common pathogenic variants for Familial Mediterranean Fever (FMF). This variant has been reported in several publications in individuals with FMF in the homozygous, heterozygous and compound heterozygous state, including a Genereviews entry describing this variant as disease causing (Selected Publications: International FMF Consortium 1997 PMID:8288758, Barut 2018 PMID:28828621, Kriegshauser 2018 PMID:29543225). This variant is present in 0.01% (12/68010) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3243407-T-C?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:2538). In summary, this variant is classified as pathogenic based on the data above.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.027%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21600797). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.41; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002538). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 10879615, 9288758). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 11977178). A different missense change at the same codon (p.Met694Ile) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002539). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This variant is a common cause of familial Mediterranean fever (FMF), and has been previously reported as a heterozygous, compound heterozygous, and homozygous change in patients with MEFV-related disorders (PMID: 9288758, 20301405). Functional studies have shown that this missense change has a damaging effect on the function of the MEFV protein (PMID: 24318677). It is present in the gnomAD population database at a frequency of 0.027% (77/282876) and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.2080A>G (p.Met694Val) variant is classified as Pathogenic.

Comment:

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 694 of the MEFV protein (p.Met694Val). This variant is present in population databases (rs61752717, gnomAD 0.04%). This missense change has been observed in individual(s) with familial Mediterranean fever (FMF) and in the homozygous state this variant is associated with a higher rate of amyloidosis and a lower response to colchicine (PMID: 9781020, 10364520, 20008920, 21290976, 22037353). 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: 2538). 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. Experimental studies have shown that this missense change affects MEFV function (PMID: 24318677). This variant disrupts the p.Met694 amino acid residue in MEFV. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10787449, 15942916, 24318677). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

The observed missense variant c.2080A>G (p.Met694Val) in MEFV gene has been reported previously in multiple individuals in both homozygous and compound heterozygous state in individuals affected with familial mediterranean fever (Grossman et al. 2018). Functional studies of this variant have shown impaired pyrin (encoded by the MEFV gene) function (Sugiyama et al. 2014). Exon 10 is a hotspot region for variants in MEFV gene causing familial mediterranean fever (Grossman et al. 2018). The p.Met694Val variant is present with an allele frequency of 0.03% (71 heterozygotes; 1 homozygote) in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Met694Val in MEFV is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 694 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

Comment:

The MEFV p.Met694Val variant is the most common variant associated with Familial Mediterranean fever (FMF), and has been identified in 1598 of 3112 proband chromosomes (frequency: 0.513) from patients with FMF (Yilmaz_2001_PMID:11464248; Tunca_2005_PMID:15643295; Domingo_2000_PMID:10854105). The variant was also identified in dbSNP (ID: rs61752717), ClinVar (classified as pathogenic by Invitae, GeneDx and nine other laboratories, and as likely pathogenic by the Swiss Institute of Bioinformatics) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 77 of 282876 chromosomes (1 homozygous) at a frequency of 0.000272 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 7 of 7226 chromosomes (freq: 0.000969), European (non-Finnish) in 59 of 129184 chromosomes (freq: 0.000457), Latino in 9 of 35438 chromosomes (freq: 0.000254) and African in 2 of 24968 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. One study of a Turkish population with FMF found that homozygosity for the M694V variant was associated with an earlier age of onset and a higher likelihood or developing arthritis and arthralgia (Tunca_2005_PMID:15643295). Individuals with the p.M694V pathogenic variant, particularly homozygous individuals, are at increased risk for amyloidosis (Dusunsel_2008_PMID:18353061) and have a decreased response to colchicine (Soylemezoglu_2010_PMID:20008920). Another study found that the M694V variant was associated with increased susceptibility to ankylosing spondylitis (OR=3.33) (Zhong_2017_PMID:28800602). The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (MaxEntScan, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity.The p.Met694 residue is not conserved in mammals and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Further, functional studies of the M694V variant have shown impaired pyrin (encoded by the MEFV gene) function (Sugiyama_2014_PMID:24318677). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Comment:

The MEFV c.2080A>G variant is predicted to result in the amino acid substitution p.Met694Val. This variant is one of the most common pathogenic variants identified in patients with familial Mediterranean fever (FMF; Moradian et al. 2013. PubMed ID: 23907647; Comak et al. 2013. PubMed ID: 23588594; Sedivá et al. 2014. PubMed ID: 24251727). This variant has been identified in patients in the homozygous and compound heterozygous states, as well as in heterozygous carriers with clinical manifestations of FMF (Moradian et al. 2013. PubMed ID: 23907647; Sedivá et al. 2014. PubMed ID: 24251727). This variant is reported in 0.046% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

Comment:

Variant interpretted as Pathogenic and reported on 06-02-2016 by Lab or GTR ID 506013. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child.	Mor-Shaked H	European journal of human genetics : EJHG	2021	PMID: 33223529
Familial Mediterranean fever (FMF) phenotype in patients homozygous to the MEFV M694V mutation.	Grossman C	European journal of medical genetics	2019	PMID: 30171907
Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.	Masters SL	Science translational medicine	2016	PMID: 27030597
Familial Mediterranean Fever.	Adam MP	-	2016	PMID: 20301405
Amyloidosis and its related factors in Turkish patients with familial Mediterranean fever: a multicentre study.	Kasifoglu T	Rheumatology (Oxford, England)	2014	PMID: 24369413
Defect of suppression of inflammasome-independent interleukin-8 secretion from SW982 synovial sarcoma cells by familial Mediterranean fever-derived pyrin mutations.	Sugiyama R	Molecular biology reports	2014	PMID: 24318677
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
Enthesopathy in patients with familial Mediterranean fever: increased prevalence in M694 V variant.	Tufan A	Rheumatology international	2013	PMID: 23334425
Homozygous M694V as a risk factor for amyloidosis in Turkish FMF patients.	Akpolat T	Gene	2012	PMID: 22037353
Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice.	Chae JJ	Immunity	2011	PMID: 21600797
Screening for the M694V mutation of the familial Mediterranean fever (FMF) gene in 604 French patients.	Bathelier C	Genetic counseling (Geneva, Switzerland)	2010	PMID: 21290976
Unresponsiveness to colchicine therapy in patients with familial Mediterranean fever homozygous for the M694V mutation.	Soylemezoglu O	The Journal of rheumatology	2010	PMID: 20008920
Familial mediterranean Fever in the world.	Ben-Chetrit E	Arthritis and rheumatism	2009	PMID: 19790133
Genotype-phenotype correlation in children with familial Mediterranean fever in a Turkish population.	Duşunsel R	Pediatrics international : official journal of the Japan Pediatric Society	2008	PMID: 18353061
Familial Mediterranean fever and peritoneal malignant mesothelioma: a possible association?	Hershcovici T	The Israel Medical Association journal : IMAJ	2006	PMID: 16889173
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
The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series.	Majeed HA	Seminars in arthritis and rheumatism	2005	PMID: 15942916
Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study.	-	Medicine	2005	PMID: 15643295
Familial Mediterranean fever: the segregation of four different mutations in 13 individuals from one inbred family: genotype-phenotype correlation and intrafamilial variability.	Gershoni-Baruch R	American journal of medical genetics	2002	PMID: 11977178
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
Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population.	Yilmaz E	European journal of human genetics : EJHG	2001	PMID: 11464248
Familial Mediterranean fever diagnosed by PCR.	Mohey R	Scandinavian journal of infectious diseases	2000	PMID: 10879615
The genetic basis of autosomal dominant familial Mediterranean fever.	Booth DR	QJM : monthly journal of the Association of Physicians	2000	PMID: 10787449
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
Phenotype-genotype correlation in Jewish patients suffering from familial Mediterranean fever (FMF).	Dewalle M	European journal of human genetics : EJHG	1998	PMID: 9781020
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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Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000243.3(MEFV):c.2080A>G (p.Met694Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61752717 ...