ClinVar Genomic variation as it relates to human health
NM_000243.3(MEFV):c.2078TGA[1] (p.Met694del)
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.
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(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000243.3(MEFV):c.2078TGA[1] (p.Met694del)
Variation ID: 2556 Accession: VCV000002556.18
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 16p13.3 16: 3243404-3243406 (GRCh38) [ NCBI UCSC ] 16: 3293404-3293406 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 20, 2014 Feb 20, 2024 Mar 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000243.3:c.2078TGA[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000234.1:p.Met694del inframe deletion NM_000243.2:c.2081_2083delTGA NM_001198536.2:c.*282TGA[1] 3 prime UTR NC_000016.10:g.3243405CAT[1] NC_000016.9:g.3293405CAT[1] NG_007871.1:g.18219TGA[1] LRG_190:g.18219TGA[1] - Protein change
- M694del
- Other names
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- Canonical SPDI
- NC_000016.10:3243403:TCATCAT:TCAT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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MEFV | No evidence available | No evidence available |
GRCh38 GRCh37 |
949 | 1246 | |
LOC126862264 | - | - | - | GRCh38 | - | 254 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Apr 1, 2000 | RCV000002665.11 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Aug 19, 2022 | RCV000083740.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 10, 2023 | RCV000757455.17 |
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. |
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Pathogenic
(Jun 13, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696057.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
Comment:
Variant summary: The MEFV c.2081_2083delTGA (p.Met694del) variant involves an in-frame deletion of three nucleotides. One in silico tool predicts a benign outcome for this variant. … (more)
Variant summary: The MEFV c.2081_2083delTGA (p.Met694del) variant involves an in-frame deletion of three nucleotides. One in silico tool predicts a benign outcome for this variant. The variant is absent in 121410 control chromosomes while it was reported in several FMF patients in heterozygosity indicating a dominant inheritance. Taken together, this variant is classified as pathogenic. (less)
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial Mediterranean fever
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139822.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Aug 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001491922.3
First in ClinVar: Mar 07, 2021 Last updated: Feb 07, 2023 |
Comment:
This variant, c.2081_2083del, results in the deletion of 1 amino acid(s) of the MEFV protein (p.Met694del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.2081_2083del, results in the deletion of 1 amino acid(s) of the MEFV protein (p.Met694del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs104895091, gnomAD 0.002%). This variant has been observed in individual(s) with Familial Mediterranean Fever (PMID: 10024914, 10787449, 19479870, 21246368, 29047407). ClinVar contains an entry for this variant (Variation ID: 2556). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MEFV function (PMID: 33733382). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Mar 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885687.2
First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024 |
Comment:
The MEFV c.2081_2083del; p.Met694del variant (rs104895091) is reported in the literature in multiple individuals and families with a clinical diagnosis of familial Mediterranean fever; individuals … (more)
The MEFV c.2081_2083del; p.Met694del variant (rs104895091) is reported in the literature in multiple individuals and families with a clinical diagnosis of familial Mediterranean fever; individuals of northern European ancestry often had clinical symptoms without an additional pathogenic variant (Booth 2000, Booty 2009, Rowczenio 2017), whereas two individuals of Moroccan ancestry had an additional pathogenic variant consistent with autosomal recessive inheritance (Belmahi 2012). This variant is also reported in ClinVar (Variation ID: 2556), but is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single methionine residue leaving the rest of the protein in-frame. Considering available information, this variant is classified as pathogenic. References: Belmahi L et al. MEFV mutations in Moroccan patients suffering from familial Mediterranean Fever. Rheumatol Int. 2012 Apr;32(4):981-4. PMID: 21246368. Booth DR et al. The genetic basis of autosomal dominant familial Mediterranean fever. QJM. 2000 Apr;93(4):217-21. PMID: 10787449. Booty MG et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 2009 Jun;60(6):1851-61. PMID: 19479870. Rowczenio DM et al. Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue-a case series and genetic exploration. Rheumatology (Oxford). 2017 Feb;56(2):209-213. PMID: 27150194. (less)
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Pathogenic
(Apr 01, 2000)
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no assertion criteria provided
Method: literature only
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FAMILIAL MEDITERRANEAN FEVER, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022823.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 03, 2016 |
Comment on evidence:
In affected members of 3 unrelated British families with autosomal dominant FMF (134610), Booth et al. (2000) identified heterozygosity for a 3-bp deletion in the … (more)
In affected members of 3 unrelated British families with autosomal dominant FMF (134610), Booth et al. (2000) identified heterozygosity for a 3-bp deletion in the MEFV gene, resulting in deletion of residue met694. This codon is the site of 2 other common mutations in the MEFV gene (M694V; 608107.0001 and M694I; 608107.0002). The clinical features of FMF in these families were classical in every respect, including favorable response to colchicine. Incomplete penetrance was observed. Only 1 patient had amyloidosis. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001462096.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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Familial Mediterranean fever
Affected status: not provided
Allele origin:
not provided
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Unité médicale des maladies autoinflammatoires, CHRU Montpellier
Accession: SCV000115833.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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not provided
(-)
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no classification provided
Method: literature only
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Familial Mediterranean fever
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000484969.2
First in ClinVar: Feb 20, 2014 Last updated: Oct 01, 2022 |
Ethnicity/Population group: Northern European, Iranian, Azari Turkish
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Rapid Flow Cytometry-Based Assay for the Functional Classification of MEFV Variants. | Honda Y | Journal of clinical immunology | 2021 | PMID: 33733382 |
A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. | Papa R | Orphanet journal of rare diseases | 2017 | PMID: 29047407 |
Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue-a case series and genetic exploration. | Rowczenio DM | Rheumatology (Oxford, England) | 2017 | PMID: 27150194 |
Clinical Review: Familial Mediterranean Fever-An Overview of Pathogenesis, Symptoms, Ocular Manifestations, and Treatment. | Petrushkin H | Ocular immunology and inflammation | 2016 | PMID: 25760918 |
Familial Mediterranean Fever. | Adam MP | - | 2016 | PMID: 20301405 |
MEFV mutations in Moroccan patients suffering from familial Mediterranean Fever. | Belmahi L | Rheumatology international | 2012 | PMID: 21246368 |
Genetics of monogenic autoinflammatory diseases: past successes, future challenges. | Aksentijevich I | Nature reviews. Rheumatology | 2011 | PMID: 21727933 |
MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever. | Bonyadi M | Clinical genetics | 2009 | PMID: 19863562 |
Familial Mediterranean fever with a single MEFV mutation: where is the second hit? | Booty MG | Arthritis and rheumatism | 2009 | PMID: 19479870 |
Clinical and molecular diagnosis of Familial Mediterranean Fever in Egyptian children. | Settin A | Journal of gastrointestinal and liver diseases : JGLD | 2007 | PMID: 17592559 |
Multiplex molecular diagnosis of MEFV mutations in patients with familial Mediterranean fever by LightCycler real-time PCR. | Rossou E | Clinical chemistry | 2005 | PMID: 16120953 |
Genetic screening of familial Mediterranean fever mutations in the Palestinian population. | Ayesh SK | Saudi medical journal | 2005 | PMID: 15951859 |
Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. | Medlej-Hashim M | BMC medical genetics | 2004 | PMID: 15018633 |
The spectrum of Familial Mediterranean Fever (FMF) mutations. | Touitou I | European journal of human genetics : EJHG | 2001 | PMID: 11464238 |
The genetic basis of autosomal dominant familial Mediterranean fever. | Booth DR | QJM : monthly journal of the Association of Physicians | 2000 | PMID: 10787449 |
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 |
Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). | Bernot A | Human molecular genetics | 1998 | PMID: 9668175 |
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Text-mined citations for rs104895091 ...
HelpRecord last updated Jun 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.