ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.2080A>G (rs61752717)

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Total submissions: 28
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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 2018-12-06 criteria provided, single submitter clinical testing M694V is the most common FMF-associated pathogenic variant. In a series of 90 patients of different ethnic groups, M694V accounted for more than 30% of the MEFV pathogenic variants identified (Aksentijevich et al., 1999). M694V has also been published in association with FMF in additional individuals (The International FMF Consortium, 1997). The variant is observed in 56/126712 (0.044%) alleles in individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). While this substitution occurs at a position in the B30.2/SPRY domain that is not conserved, functional studies have shown that M694V has a damaging effect on the function of the MEFV protein (Sugiyama et al., 2014). Missense variants in the same residue (M694I/K) and in a nearby residue (K695R/M) have been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.
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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000216751 SCV000331542 pathogenic not provided 2016-08-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999741 SCV000604181 pathogenic none provided 2020-08-27 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% (74/277222 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. 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. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001 9(7):478-483.
Invitae RCV000002647 SCV000629034 pathogenic Familial Mediterranean fever 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 694 of the MEFV protein (p.Met694Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs61752717, ExAC 0.04%). This variant is the most common cause of familial Mediterranean fever (FMF) in Israel, Armenia and Turkey, although it is also present in other populations (PMID: 9781020, 10364520, 21290976, 22037353). In the homozygous state this variant is associated with a higher rate of amyloidosis and a lower response to colchicine (PMID: 20008920, 22037353). ClinVar contains an entry for this variant (Variation ID: 2538). Experimental studies have shown that this missense change reduces the suppression of IL8 secretion by MEFV in synovial cell cultures (PMID: 24318677). A different missense substitution at this codon (p.Met694Ile) has been determined to be pathogenic (PMID: 10787449, 15942916, 24318677). This suggests that the methionine residue is critical for MEFV protein function and that other missense substitutions at this position may also be pathogenic. 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.
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735284 SCV000854437 pathogenic Cryptorchidism; Global developmental delay; Seizures; Abnormality of the anterior fontanelle; Macrocephalus; Deep plantar creases; Abnormality of the cerebral white matter; Central hypotonia criteria provided, single submitter clinical testing
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735306 SCV000854459 pathogenic Brachydactyly; Autistic behavior; Stereotypy; Abnormal facial shape; Synophrys; Microcephaly; Impaired use of nonverbal behaviors; 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 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Myriad Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV000216751 SCV001245670 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
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 Karolinska University Hospital,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 2020-12-22 criteria provided, single submitter clinical testing PS4, PS3_moderate, PM1, PM3, PP5
OMIM RCV000002647 SCV000022805 pathogenic Familial Mediterranean fever 2010-01-01 no assertion criteria provided literature only
GeneReviews RCV000002647 SCV000484968 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria 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.

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