ClinVar Genomic variation as it relates to human health
NM_000243.3(MEFV):c.2076_2078del (p.Ile692del)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000243.3(MEFV):c.2076_2078del (p.Ile692del)
Variation ID: 97485 Accession: VCV000097485.32
- Type and length
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Deletion, 3 bp
- Location
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Cytogenetic: 16p13.3 16: 3243409-3243411 (GRCh38) [ NCBI UCSC ] 16: 3293409-3293411 (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 Apr 4, 2013 Jun 17, 2024 Nov 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000243.3:c.2076_2078del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000234.1:p.Ile692del NM_000243.2:c.2076_2078delAAT NM_001198536.2:c.*280_*282del NC_000016.10:g.3243411_3243413del NC_000016.9:g.3293411_3293413del NG_007871.1:g.18217_18219del LRG_190:g.18217_18219del - Protein change
- I692del
- Other names
- I692delI
- MEFV, 3-BP DEL, ILE692DEL
- Canonical SPDI
- NC_000016.10:3243408:ATTAT:AT
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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 |
954 | 1254 | |
LOC126862264 | - | - | - | GRCh38 | - | 256 |
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
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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/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 20, 2023 | RCV000083737.23 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Aug 29, 2023 | RCV000487146.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2022 | RCV002262640.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2023 | RCV003460764.2 |
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
(Feb 20, 2019)
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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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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134280.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 03, 2022 |
Comment:
The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Occurs in … (more)
The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Occurs in multiple cases with a recessive pathogenic variant in the same gene. (less)
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial Mediterranean fever
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318574.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
nframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function(PM4_M). The variant has been reported … (more)
nframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function(PM4_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000097485, PMID:9668175). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008). The variant is observed to be in trans with the other variant (3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abdominal distention (present) , Fever (present) , Hepatomegaly (present) , Hypochromic microcytic anemia (present) , Reticulocytopenia (present) , Splenomegaly (present)
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Pathogenic
(Mar 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002543731.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Likely pathogenic
(Sep 14, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003833988.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 29, 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: SCV001158041.2
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The MEFV c.2076_2078delAAT; p.Ile692del variant (rs104895093), is reported in the literature in multiple individuals affected with familial Mediterranean fever (FMF) (Aoki 2022, Bernot 1998, Platt … (more)
The MEFV c.2076_2078delAAT; p.Ile692del variant (rs104895093), is reported in the literature in multiple individuals affected with familial Mediterranean fever (FMF) (Aoki 2022, Bernot 1998, Platt 2021, Salehzadeh 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 97485), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single isoleucine residue leaving the rest of the protein in-frame. Functional analyses demonstrate increased cell death compared to wild-type, similar to other known pathogenic variants (Aoki 2022, Honda 2021). This variant affects a residue in the conserved region of the B30.2 domain, which contains pathogenic MEFV variants associated with the most severe FMF symptoms (Moradian 2017). Based on available information, the p.Ile692del variant is considered to be pathogenic. References: Aoki M et al. Case Report: A Pediatric Case of Familial Mediterranean Fever Concurrent With Autoimmune Hepatitis. Front Immunol. 2022 Jun 24;13:917398. PMID: 35812376. Bernot A et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. PMID: 9668175. Honda Y et al. Rapid Flow Cytometry-Based Assay for the Functional Classification of MEFV Variants. J Clin Immunol. 2021 Aug;41(6):1187-1197. PMID: 33733382. Moradian MM et al. Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF. Mol Genet Genomic Med. 2017 Nov;5(6):742-750. PMID: 29178647. Platt CD et al. Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency. J Allergy Clin Immunol. 2021 Feb;147(2):723-726. PMID: 32888943. Salehzadeh F et al. MEFV Gene Profile in Northwest of Iran, Twelve Common MEFV Gene Mutations Analysis in 216 Patients with Familial Mediterranean Fever. Iran J Med Sci. 2015 Jan;40(1):68-72. PMID: 25648235. (less)
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Pathogenic
(Nov 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial Mediterranean fever, autosomal dominant
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004194414.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Oct 14, 2014)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000224796.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Sep 16, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449622.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000565123.5
First in ClinVar: Apr 27, 2017 Last updated: Mar 11, 2023 |
Comment:
Published functional studies demonstrate this variant has a deleterious effect on protein function (Honda et al., 2021); In-frame deletion of 1 amino acid in a … (more)
Published functional studies demonstrate this variant has a deleterious effect on protein function (Honda et al., 2021); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19253030, 22975760, 23907647, 9668175, 10737995, 25648235, 26892483, 29543225, 32888943, 35812376, 19302049, 29379228, 28302131, 29047407, 17566872, 33733382) (less)
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Likely pathogenic
(Mar 20, 2023)
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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: SCV003922579.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: MEFV c.2076_2078delAAT (p.Ile692del) results in an in-frame deletion that is predicted to remove one amino acid, Ile692, from the SPRY domain (IPR003877) of … (more)
Variant summary: MEFV c.2076_2078delAAT (p.Ile692del) results in an in-frame deletion that is predicted to remove one amino acid, Ile692, from the SPRY domain (IPR003877) of the encoded protein. The variant allele was found at a frequency of 7.9e-06 in 252200 control chromosomes (gnomAD and publications). c.2076_2078delAAT has been reported in the literature in the compound heterozygous and heterozygous state in multiple individuals affected with Familial Mediterranean Fever across several countries, including cases where it has been observed in trans with a pathogenic variant (e.g. Bernot_1998, Tchernitchko_2003, Medlej-Hashim_2005, Chaabouni_2007, Singh-Grewal_2007, Sabbagh_2008, El Garf_2010, Jardour_2010, Berdeli_2011, Salehzadeh_2015, Ait-Idir_2017). These data indicate that the variant is likely to be associated with disease. However, this variant mostly associates in cis with p.E148Q, a common variant with controversial pathogenicity and/or low penetrance and thus, there are fewer cases where the variant has been observed in isolation from which to definitively determine its association to the disease phenotype. At least one publication reports experimental evidence evaluating an impact of the variant on protein function (Honda_2021) and found that the variant was more responsive to TcdA- and UCN-01-induced cell death compared to the WT protein, suggesting it has an effect on protein function, yet the significance of this finding in a clinical context are not clear. Therefore this study does not allow for unequivocal conclusions about the variant effect. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=5)/likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic until further evidence (i.e. homozygous occurrences in patients, cosegregation of the variant with FMF and/or additional functional studies) is available. (less)
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Pathogenic
(Aug 01, 1998)
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no assertion criteria provided
Method: literature only
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FAMILIAL MEDITERRANEAN FEVER
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022813.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In an Arab family with familial Mediterranean fever (FMF; 249100), Bernot et al. (1998) observed deletion of AAT from 2 adjacent codons (ile692 and met693) … (more)
In an Arab family with familial Mediterranean fever (FMF; 249100), Bernot et al. (1998) observed deletion of AAT from 2 adjacent codons (ile692 and met693) in exon 10 of the MEFV gene, resulting in transformation into a single ATG codon after the deletion (ile692del) and conservation of the reading frame. The mutation was not found in any of 198 control chromosomes. (less)
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Likely pathogenic
(Mar 15, 2019)
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no assertion criteria provided
Method: clinical testing
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Familial Mediterranean fever
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132430.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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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:
unknown
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Unité médicale des maladies autoinflammatoires, CHRU Montpellier
Accession: SCV000115830.1
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: SCV000484967.2
First in ClinVar: Nov 18, 2016 Last updated: Oct 01, 2022 |
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Uncertain significance
(Nov 26, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Familial Mediterranean fever
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001215382.1
First in ClinVar: Apr 15, 2020 Last updated: Apr 15, 2020 |
Comment:
This variant, c.2076_2078del, results in the deletion of 1 amino acid(s) of the MEFV protein (p.Ile692del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.2076_2078del, results in the deletion of 1 amino acid(s) of the MEFV protein (p.Ile692del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with familial mediterranean fever (PMID: 29047407, 9668175, 21246368, 15018633, 22019805, 29379228, 25648235, 21413889, 28302131, 14578331, 19253030, 17566872). ClinVar contains an entry for this variant (Variation ID: 97485). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. 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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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 |
Small Intestinal Bacterial Overgrowth Affects the Responsiveness to Colchicine in Familial Mediterranean Fever. | Verrecchia E | Mediators of inflammation | 2017 | PMID: 29379228 |
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 |
A survey of resistance to colchicine treatment for French patients with familial Mediterranean fever. | Corsia A | Orphanet journal of rare diseases | 2017 | PMID: 28302131 |
The M694I/M694I genotype: A genetic risk factor of AA-amyloidosis in a group of Algerian patients with familial Mediterranean fever. | Ait-Idir D | European journal of medical genetics | 2017 | PMID: 27956278 |
Familial Mediterranean Fever. | Adam MP | - | 2016 | PMID: 20301405 |
MEFV Gene Profile in Northwest of Iran, Twelve Common MEFV Gene Mutations Analysis in 216 Patients with Familial Mediterranean Fever. | Salehzadeh F | Iranian journal of medical sciences | 2015 | PMID: 25648235 |
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 |
MEFV mutations in Moroccan patients suffering from familial Mediterranean Fever. | Belmahi L | Rheumatology international | 2012 | PMID: 21246368 |
Spectrum of mutations and carrier frequency of familial Mediterranean fever gene in the Algerian population. | Ait-Idir D | Rheumatology (Oxford, England) | 2011 | PMID: 22019805 |
Comprehensive analysis of a large-scale screen for MEFV gene mutations: do they truly provide a "heterozygote advantage" in Turkey? | Berdeli A | Genetic testing and molecular biomarkers | 2011 | PMID: 21413889 |
Prevalence of known mutations in the MEFV gene in a population screening with high rate of carriers. | Ozdemir O | Molecular biology reports | 2011 | PMID: 20165923 |
Genotype-phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations. | Moradian MM | Journal of human genetics | 2010 | PMID: 20485448 |
MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations. | el-Garf A | Rheumatology international | 2010 | PMID: 19777236 |
Familial Mediterranean fever in Syrian patients: MEFV gene mutations and genotype-phenotype correlation. | Jarjour RA | Molecular biology reports | 2010 | PMID: 19253030 |
Prevalence of known mutations in the familial Mediterranean fever gene (MEFV) in various carrier screening populations. | Mikula M | Genetics in medicine : official journal of the American College of Medical Genetics | 2008 | PMID: 18496034 |
MEFV gene mutations spectrum among Lebanese patients referred for Familial Mediterranean Fever work-up: experience of a major tertiary care center. | Sabbagh AS | Molecular biology reports | 2008 | PMID: 17566872 |
Coexistent MEFV and CIAS1 mutations manifesting as familial Mediterranean fever plus deafness. | Singh-Grewal D | Annals of the rheumatic diseases | 2007 | PMID: 17934081 |
MEFV mutations in Tunisian patients suffering from familial Mediterranean fever. | Chaabouni HB | Seminars in arthritis and rheumatism | 2007 | PMID: 17276496 |
Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. | Medlej-Hashim M | European journal of medical genetics | 2005 | PMID: 16378925 |
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 |
Clinical evaluation of a reverse hybridization assay for the molecular detection of twelve MEFV gene mutations. | Tchernitchko D | Clinical chemistry | 2003 | PMID: 14578331 |
Genetic screening of fourteen mutations in Jordanian familial Mediterranean fever patients. | Medlej-Hashim M | Human mutation | 2000 | PMID: 10737992 |
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 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MEFV | - | - | - | - |
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Text-mined citations for rs104895093 ...
HelpRecord last updated Oct 13, 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.