rs28940578

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000243.3(MEFV):c.2082G>A(p.Met694Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M694K) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

MEFV
NM_000243.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:39O:1

Conservation

PhyloP100: -1.13

Variant links:

Genes affected

MEFV (HGNC:6998): (MEFV innate immunity regulator, pyrin) This gene encodes a protein, also known as pyrin or marenostrin, that is an important modulator of innate immunity. Mutations in this gene are associated with Mediterranean fever, a hereditary periodic fever syndrome. [provided by RefSeq, Jul 2008]

MEFV links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a strand (size 7) in uniprot entity MEFV_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000243.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-3243406-A-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant 16-3243405-C-T is Pathogenic according to our data. Variant chr16-3243405-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3243405-C-T is described in Lovd as [Pathogenic]. Variant chr16-3243405-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEFV	NM_000243.3 link	c.2082G>A	p.Met694Ile	missense_variant	Exon 10 of 10	ENST00000219596.6	NP_000234.1	O15553-2
MEFV	NM_001198536.2 link	c.*286G>A		3_prime_UTR_variant	Exon 9 of 9		NP_001185465.2	O15553-3D2DTW2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6 link	c.2082G>A	p.Met694Ile	missense_variant	Exon 10 of 10	1	NM_000243.3	ENSP00000219596.1		O15553-2

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251490

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000841

AC:

123

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000549

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000383

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:39Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial Mediterranean fever

Pathogenic:15Other:1

Sep 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met694Ile variant in MEFV is one of the most commonly reported pathogenic variant (both in the homozygous and compound heterozygous state) in individuals with familial Mediterranean fever (examples: Majeed 2005 PMID: 15942916, Moradian 2014 PMID: 23907647). It has been reported in ClinVar ( Variation ID 2539) and has been identified in 1/316 Middle Eastern and 3/5196 East Asian chromosomes (among other population where the variant freqency is lower) by gnomAD ((http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant affects the level of IL8 secretion (Sugiyama 2014 PMID: 24318677). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive familial Mediterranean fever. ACMG/AMP Criteria applied: PM2_Supporting, PM3_VeryStrong, PS3_Supporting. -

Jul 18, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM1, PM5, PM2, PP5, BP4 -

Sep 08, 2023

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10612841, 16378925). he 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: 16378925) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 12064853). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001427). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002538,VCV000449657, PMID:23031807,NULL,9288758). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 04, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000243.2(MEFV):c.2082G>A(M694I) is classified as pathogenic in the context of familial Mediterranean fever. Please note that in the absence of a known personal and/or family history of inflammatory disease, the clinical significance of this MEFV variant status is uncertain. Sources cited for classification include the following: PMID 9288094, 10612841, 16378925, 19863562, 11938447, and 16378925. Classification of NM_000243.2(MEFV):c.2082G>A(M694I) 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. -

Feb 17, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM3_VeryStrong, PM2, PS3, PM5 -

Apr 11, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2023

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 694 of the MEFV protein (p.Met694Ile). This variant is present in population databases (rs28940578, gnomAD 0.05%). This missense change has been observed in individuals with familial Mediterranean fever (PMID: 10787449, 12064853, 15168590, 15805719, 20051664). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2539). 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: 9781020, 10364520, 12064853, 21290976, 22037353). 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. -

not provided

Pathogenic:14

Jun 02, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 14, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 22, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV: PM3:Very Strong, PM1, PM5, PM2:Supporting, PS3:Supporting, BP4 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 15, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM1, PM3_very_strong, PM5, PS3, PS4 -

Jun 15, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that M694I alters the level of IL8 secretion in vitro (Sugiyama et al., 2014); This variant is associated with the following publications: (PMID: 26413094, 26399837, 27150194, 26400644, 25393764, 25286988, 25449140, 25528861, 26003477, 24286006, 23907647, 21727109, 10090880, 19863562, 11938447, 12924509, 10787449, 11175300, 26299986, 24318677, 24533546, 26074413, 26173767, 15942916, 22975760, 24593212, 22766764, 20051664, 15168590, 23461592, 15805719, 12064853, 27181238, 16704654, 19480334, 9288094, 17711558, 16730661, 16378925, 10612841, 10234504, 10024914, 29543225, 28828621, 32199921, 29080837, 31589614, 33440462, 10842289, 10852276, 10662876) -

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEFV c.2082G>A;p.Met694Ile variant (rs28940578) is reported as a common familial Mediterranean fever (FMF) pathogenic variant (Majeed 2005, Moradian 2014). The variant is listed in the ClinVar database (Variation ID: 2539). This variant is found in the general population with an overall allele frequency of 0.01% (36/282886 alleles) in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. References: Majeed HA et al. The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum. 2005. 34(6):813-8. PMID: 15942916 Moradian MM et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 16(3):258-63. PMID: 23907647 -

Oct 10, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial Mediterranean fever, autosomal dominant

Pathogenic:4

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with familial Mediterranean fever (FMF; MIM#134610, MIM# 249100). Gain of function is a mechanism demonstrated by mouse models (PMID: 21600797). However, there has been some controversy as to whether this is due to a loss of an inhibitor or gain of pro-inflammatory function (PMID: 31088470). (I) 0108 - This gene is associated with both recessive and dominant disease. FMF is mostly autosomal recessive, however approximately 31% of patients with clinical FMF lack a second disease-associated variant (PMID: 29393966, PMID: 31088470). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been reported for variants in this gene (PMID: 11528510, PMID: 29393966). Penetrance for autosomal dominant FMF is incomplete, and the clinical severity is less than in autosomal recessive FMF (PMID: 20301405). (I) 0115 - Variants in this gene are known to have variable expressivity. There is variability of clinical symptoms in patients carrying the same mutations, even within the same family (PMID: 29393966). Previous studies have identified significant effects of modifying genes and environmental factors on the clinical phenotypes (PMID: 31088470). 0200 - Variant is predicted to result in a missense amino acid change from methionine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (36 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (75 heterozygotes, 1 homozygote). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated SPRY domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified multiple times as pathogenic, and is one of the most common alleles in individuals with familial Mediterranean fever. It has been observed in heterozygous, compound heterozygous and homozygous affected individuals. Additionally, individuals homozygous for this variant are more likely to develop renal amyloidosis (InFevers, ClinVar, GeneReviews, PMID: 27956278, PMID: 35490273, PMID: 32676558). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Oct 04, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2017

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant

Pathogenic:2

Feb 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant

Pathogenic:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2017

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEFV NM_000243.2 exon 10 p.Met694Ile (c.2082G>A): This variant is one of the most common pathogenic mutations associated with Familial Mediterranian Fever. This variant has been reported in several publications, including a GeneReviews entry describing this variant as disease causing (Shothat 2016 PMID:20301405). This variant is present in 17/12674 European individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28940578). 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:2539). In summary, this variant is classified as pathogenic based on the data above. -

Autoinflammatory syndrome

Pathogenic:1

Mar 25, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MEFV-related disorder

Pathogenic:1

May 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MEFV c.2082G>A variant is predicted to result in the amino acid substitution p.Met694Ile. This variant has previously been reported to be causative for familial Mediterranean fever (Gershoni-Baruch et al. 2002. PubMed ID: 11938447; Moradian et al. 2014. PubMed ID: 23907647; Cazeneuve et al. 1999. PubMed ID: 10364520). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

7.3

DANN

Benign

0.64

DEOGEN2

Benign

0.38

T;.;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.13

T;T;T

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.96

L;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.8

N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.79

P;.;.

Vest4

0.30

MutPred

0.88

Loss of catalytic residue at M694 (P = 0.0144);.;.;

MVP

0.65

MPC

0.15

ClinPred

0.40

GERP RS

-1.8

Varity_R

0.36

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over