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

gnomAD frequency: 0.00012  dbSNP: rs61752717

Total submissions: 49

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002647	SCV000052840	pathogenic	Familial Mediterranean fever	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
GeneDx	RCV000216751	SCV000279058	pathogenic	not provided	2020-07-15	criteria provided, single submitter	clinical testing	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)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000216751	SCV000281543	pathogenic	not provided	2014-11-24	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000216751	SCV000331542	pathogenic	not provided	2016-08-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000216751	SCV000604181	pathogenic	not provided	2023-11-22	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000002647	SCV000629034	pathogenic	Familial Mediterranean fever	2024-01-29	criteria provided, single submitter	clinical testing	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.
SIB Swiss Institute of Bioinformatics	RCV000002647	SCV000803512	likely pathogenic	Familial Mediterranean fever	2018-05-31	criteria provided, single submitter	curation	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.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735284	SCV000854437	pathogenic	Cryptorchidism; Global developmental delay; Seizure; Abnormality of the anterior fontanelle; Macrocephaly; Deep plantar creases; Abnormal cerebral white matter morphology; Central hypotonia		criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735306	SCV000854459	pathogenic	Brachydactyly; Autistic behavior; Stereotypic movement disorder; Abnormal facial shape; Synophrys; Microcephaly; Abnormal nonverbal communicative behavior; Generalized hypotonia; Profound global developmental delay		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763381	SCV000894080	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000002647	SCV001139826	pathogenic	Familial Mediterranean fever	2022-05-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000002647	SCV001193946	pathogenic	Familial Mediterranean fever	2019-10-18	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000216751	SCV001245670	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MEFV: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP1, BP4
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001028046	SCV001251817	likely pathogenic	Familial Mediterranean fever, autosomal dominant	2020-05-03	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197704	SCV001368483	pathogenic	Acute febrile neutrophilic dermatosis	2020-02-25	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PS4_Supp,PM1,PM3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001028046	SCV001429245	pathogenic	Familial Mediterranean fever, autosomal dominant	2019-12-09	criteria provided, single submitter	clinical testing
Hadassah Hebrew University Medical Center	RCV000002647	SCV001437667	pathogenic	Familial Mediterranean fever	2019-06-20	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000216751	SCV001447043	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000763381	SCV001448264	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant	2020-10-04	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000216751	SCV001450237	pathogenic	not provided	2014-07-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001028046	SCV001524568	pathogenic	Familial Mediterranean fever, autosomal dominant	2019-11-19	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000216751	SCV001712843	pathogenic	not provided	2022-09-14	criteria provided, single submitter	clinical testing	PP5, PM1, PS3, PS4_moderate
Fulgent Genetics, Fulgent Genetics	RCV001535935	SCV001752593	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-06-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000002647	SCV001810497	pathogenic	Familial Mediterranean fever	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000216751	SCV002017261	pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000002647	SCV002072563	pathogenic	Familial Mediterranean fever	2023-09-20	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM5
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000763381	SCV002495841	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant	2021-05-03	criteria provided, single submitter	clinical testing	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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262539	SCV002543732	pathogenic	Autoinflammatory syndrome	2022-04-19	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001028046	SCV002580916	pathogenic	Familial Mediterranean fever, autosomal dominant	2022-08-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415387	SCV002726824	pathogenic	Inborn genetic diseases	2018-02-06	criteria provided, single submitter	clinical testing	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.
Human Genetics Bochum, Ruhr University Bochum	RCV001028046	SCV002758595	pathogenic	Familial Mediterranean fever, autosomal dominant	2022-05-06	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PP1, PS3, PM1, PS4, PM5
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001028046	SCV003807537	pathogenic	Familial Mediterranean fever, autosomal dominant	2023-02-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 very strong, PM5 moderated, PP1 strong
3billion	RCV000002647	SCV003841560	pathogenic	Familial Mediterranean fever	2023-02-23	criteria provided, single submitter	clinical testing	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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000216751	SCV004026421	pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing	PS4, PS3, PM3
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV003325449	SCV004032056	pathogenic	Recurrent fever	2023-09-06	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335011	SCV004046213	pathogenic	MEFV-related disorder		criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000002647	SCV004847545	pathogenic	Familial Mediterranean fever	2022-06-23	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000002647	SCV000022805	pathogenic	Familial Mediterranean fever	2010-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000002647	SCV000484968	not provided	Familial Mediterranean fever		no assertion provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV001028046	SCV001190817	pathogenic	Familial Mediterranean fever, autosomal dominant	2020-02-05	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000002647	SCV001423313	not provided	Familial Mediterranean fever		no assertion provided	phenotyping only	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.
Natera, Inc.	RCV000002647	SCV001462098	pathogenic	Familial Mediterranean fever	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000216751	SCV001550173	pathogenic	not provided		no assertion criteria provided	clinical testing	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 laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000216751	SCV001744126	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000216751	SCV001807357	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000216751	SCV001929715	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000216751	SCV001952766	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000216751	SCV001973494	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV001028046	SCV004041643	pathogenic	Familial Mediterranean fever, autosomal dominant	2023-10-09	no assertion criteria provided	clinical testing