ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.2080A>G (p.Met694Val) (rs61752717)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000216751 SCV000604181 pathogenic not provided 2017-06-12 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.
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
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
Counsyl RCV000002647 SCV000677995 pathogenic Familial Mediterranean fever 2015-12-07 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
Fulgent Genetics RCV000763381 SCV000894080 pathogenic Familial Mediterranean fever; Familial mediterranean fever, autosomal dominant 2018-10-31 criteria provided, single submitter clinical testing
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.
GeneReviews RCV000002647 SCV000484968 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000002647 SCV000052840 pathogenic Familial Mediterranean fever 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000002647 SCV000629034 pathogenic Familial Mediterranean fever 2018-06-26 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.
OMIM RCV000002647 SCV000022805 pathogenic Familial Mediterranean fever 2010-01-01 no assertion criteria provided literature only
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.

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