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

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(1);Pathogenic(10);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
14 (Most recent: Oct 22, 2019)
Last evaluated:
May 28, 2019
Accession:
VCV000002538.4
Variation ID:
2538
Description:
single nucleotide variant
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NM_000243.2(MEFV):c.2080A>G (p.Met694Val)

Allele ID
17577
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
16p13.3
Genomic location
16: 3243407 (GRCh38) GRCh38 UCSC
16: 3293407 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000016.10:g.3243407T>C
NC_000016.9:g.3293407T>C
NM_001198536.1:c.*284A>G 3 prime UTR
... more HGVS
Protein change
M694V
Other names
NM_000243.2(MEFV):c.2080A>G(p.Met694Val)
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (C)

Allele frequency
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00028
Exome Aggregation Consortium (ExAC) 0.00023
The Genome Aggregation Database (gnomAD) 0.00019
Trans-Omics for Precision Medicine (TOPMed) 0.00018
Links
UniProtKB: O15553#VAR_009062
OMIM: 608107.0001
dbSNP: rs61752717
ClinGen: CA280091
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 4 criteria provided, multiple submitters, no conflicts Dec 6, 2018 RCV000216751.5
Pathogenic 1 criteria provided, single submitter - RCV000735284.1
Pathogenic 1 criteria provided, single submitter - RCV000735306.1
Pathogenic 1 criteria provided, single submitter Oct 31, 2018 RCV000763381.1
Conflicting interpretations of pathogenicity 7 criteria provided, conflicting interpretations May 28, 2019 RCV000002647.10
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
MEFV No evidence available No evidence available GRCh38
GRCh37
428 471

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Dec 07, 2015)
criteria provided, single submitter
Method: clinical testing
Familial Mediterranean fever
Allele origin: unknown
Counsyl
Accession: SCV000677995.1
Submitted: (Jun 22, 2017)
Evidence details
Publications
PubMed (10)
Pathogenic
(Jun 12, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604181.2
Submitted: (Oct 10, 2018)
Evidence details
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)
Pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Familial mediterranean fever, autosomal dominant
Familial Mediterranean fever
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000894080.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Pathogenic
(Dec 06, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000279058.9
Submitted: (Jan 29, 2019)
Evidence details
Comment:
M694V is the most common FMF-associated pathogenic variant. In a series of 90 patients of different ethnic groups, M694V accounted for more than 30% of ... (more)
pathogenic
(Aug 18, 2011)
criteria provided, single submitter
Method: curation, clinical testing
Familial Mediterranean Fever
(autosomal recessive)
Allele origin: germline
Integrated Genetics/Laboratory Corporation of America
Accession: SCV000052840.1
Submitted: (Aug 18, 2011)
Evidence details
Publications
PubMed (1)
Comment:
Converted during submission to Pathogenic.
Pathogenic
(Nov 24, 2014)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics
Accession: SCV000281543.1
Submitted: (May 19, 2016)
Evidence details
Likely pathogenic
(May 31, 2018)
criteria provided, single submitter
Method: curation
Familial Mediterranean fever
Allele origin: unknown
SIB Swiss Institute of Bioinformatics
Accession: SCV000803512.1
Submitted: (Jun 13, 2018)
Evidence details
Publications
PubMed (1)
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)
Pathogenic
(Aug 19, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics
Accession: SCV000331542.4
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/em...
Pathogenic
(-)
criteria provided, single submitter
Method: clinical testing
Abnormality of the anterior fontanelle
Abnormality of the cerebral white matter
Central hypotonia
Cryptorchidism
Deep plantar creases
Global developmental delay
Macrocephalus
Seizures
Allele origin: germline
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles
Accession: SCV000854437.1
Submitted: (Nov 19, 2018)
Evidence details
Pathogenic
(-)
criteria provided, single submitter
Method: clinical testing
Abnormal facial shape
Autistic behavior
Brachydactyly
Generalized hypotonia
Impaired use of nonverbal behaviors
Microcephaly
Profound global developmental delay
Stereotypy
Synophrys
Allele origin: germline
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles
Accession: SCV000854459.1
Submitted: (Nov 19, 2018)
Evidence details
Pathogenic
(Dec 31, 2018)
criteria provided, single submitter
Method: clinical testing
Familial Mediterranean fever
Allele origin: germline
Invitae
Accession: SCV000629034.4
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (9)
Comment:
This sequence change replaces methionine with valine at codon 694 of the MEFV protein (p.Met694Val). The methionine residue is weakly conserved and there is a ... (more)
Uncertain significance
(May 28, 2019)
criteria provided, single submitter
Method: clinical testing
Familial Mediterranean fever
Allele origin: unknown
Mendelics
Accession: SCV001139826.1
Submitted: (Oct 22, 2019)
Evidence details
Pathogenic
(Jan 01, 2010)
no assertion criteria provided
Method: literature only
FAMILIAL MEDITERRANEAN FEVER
Allele origin: germline
OMIM
Accession: SCV000022805.1
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (6)
Pathogenic
(Dec 15, 2016)
no assertion criteria provided
Method: literature only
Familial Mediterranean fever
Allele origin: germline
GeneReviews
Accession: SCV000484968.1
Submitted: (Dec 15, 2016)
Evidence details
Publications
PubMed (4)
Other databases
https://www.ncbi.nlm.nih.gov/b...

Citations for this variant

Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Familial Mediterranean Fever Shohat M - 2016 PMID: 20301405
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
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
Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. Rodriguez-Flores JL Human mutation 2014 PMID: 24123366
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
Three family members with familial Mediterranean fever carrying the M694V mutation showed different clinical presentations. Erten S Internal medicine (Tokyo, Japan) 2012 PMID: 22790142
Homozygous M694V as a risk factor for amyloidosis in Turkish FMF patients. Akpolat T Gene 2012 PMID: 22037353
'Silent' carriage of two familial Mediterranean fever gene mutations in large families with only a single identified patient. Camus D Clinical genetics 2012 PMID: 21995303
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. Du┼čunsel 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. Tunca M Medicine 2005 PMID: 15643295
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
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
Pyrin/marenostrin mutations in familial Mediterranean fever. Booth DR QJM : monthly journal of the Association of Physicians 1998 PMID: 10024914
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 - - - -
https://www.ncbi.nlm.nih.gov/books/NBK1227/ - - - -

Record last updated Jan 09, 2020