ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.2084A>G (rs104895094)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000002656 SCV000223936 pathogenic Familial Mediterranean fever 2015-01-05 criteria provided, single submitter clinical testing
GeneDx RCV000213470 SCV000279060 pathogenic not provided 2018-09-18 criteria provided, single submitter clinical testing The K695R variant in the MEFV gene has been reported previously in either the homozygous state or along with another pathogenic MEFV variant in multiple unrelated patients with familial Mediterranean fever (Moradian et al., 2014; Bernot et al., 1998; Caglayan et al., 2010; Oztuzcu et al., 2014; Oksuz et al., 2016). In a series of 90 patients of different ethnic groups, K695R accounted for approximately 3% of the MEFV variants identified (Aksentijevich et al., 1999). The variant is observed in 1,634/277,244 (0.6%) alleles in large population cohorts, including 11 homozygotes (Lek et al., 2016). Population data in combination with evidence from the literature suggests K695R may be a variant with a mild effect or reduced penetrance. The K695R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs within the B30.2/SPRY domain, a mutational hot spot for MEFV pathogenic variants (Masters et al., 2009). We interpret K695R as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000213470 SCV000331540 likely pathogenic not provided 2016-02-24 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000213470 SCV000493146 uncertain significance not provided 2020-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283566 SCV000604187 pathogenic none provided 2020-07-04 criteria provided, single submitter clinical testing The MEFV c.2084A>G; p.Lys695Arg variant (rs104895094) is reported in the medical literature in individuals with familial Mediterranean fever (FMF) as well as in individuals with other autoinflammatory diseases and has been implicated as a reduced penetrance allele (Altug 2013, Bernot 1998, Comak 2013, Feng 2009, Gershoni-Baruch 2002). The variant is listed in the ClinVar database (Variation ID: 2547). This variant is found in the general population with an overall allele frequency of 0.5% (1634/277224 alleles, including 11 homozygotes) in the Genome Aggregation Database. The lysine at codon 695 is moderately conserved and computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Considering available information, this variant is classified as pathogenic, but may exhibit reduced penetrance. References: Altug U et al. MEFV gene mutations in Henoch-Schonlein purpura. Int J Rheum Dis. 2013 Jun;16(3):347-51. Bernot et al. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 7(8):1317-25. Comak et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 172(8):1061-7. Feng J et al. Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels. PLoS One. 2009 Dec 30;4(12):e8480. Gershoni-Baruch et al. Familial Mediterranean fever: the segregation of four different mutations in 13 individuals from one inbred family: genotype-phenotype correlation and intrafamilial variability. Am J Med Genet. 2002 109(3):198-201.
Invitae RCV000002656 SCV000629035 likely benign Familial Mediterranean fever 2020-12-02 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 695 of the MEFV protein (p.Lys695Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs104895094, gnomAD 1.6%) including 11 homozygotes. This variant has been reported in the literature in many individuals affected with familial mediterranean fever (FMF), as compound heterozygous in the presence of a second pathogenic variant or heterozygous without an identified second pathogenic variant. This variant is also present in healthy controls and clinically asymptomatic individuals (PMID: 22037353, 9668175, 24251727, 27364639, 21413889, 22057232, 26247045). Many studies of this variant have small sample sizes and/or only examine selected exons or variants in the MEFV gene. Segregation analysis shows lack of segregation in an affected family (PMID: 1977178). ClinVar contains an entry for this variant (Variation ID: 2547). An ex vivo colchicine functional assay showed that the functional response in patients with this variant was similar to healthy controls (PMID: 32312770). The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In summary, while this variant has been reported in the literature in many individuals affected with FMF, it is observed at a higher frequency in population databases and in healthy controls and does not segregate with disease in one family. Based on the available evidence it has been classified as likely benign.
Counsyl RCV000002656 SCV000678038 likely pathogenic Familial Mediterranean fever 2017-04-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000508192 SCV000711415 uncertain significance not specified 2018-02-02 criteria provided, single submitter clinical testing Notes from review: Personal communication by Dr. Serge Amselem (who has been wor king on FMF for many years now): ...the issue of the pathogenicity of MEFV varia nts can be summarized as follows: no functional assay, conservation cannot be u sed as an argument because the domain that contains the mutations that are accep ted by the scientific community as such is not conserved in the mouse; in additi on, in other species where the domain is conserved the mutation corresponds to the reference sequence in these species. So, the only argument can be the freque ncy in the patient population versus cohort populations of the same origin. For K695R there is no proof that the variant is indeed deleterious. There are more than 30 papers reporting this variant since the original paper by Bernot-1998. I t is considered as a variant with reduced penetrance. In the paper by Gershoni-2 002 it is worth noting the high number of healthy individuals that carry the var iant in the family (and none of the affecteds). In the paper by Aksientevitch-1 999 the K695 is found more often in healthy controls than in patients [....The K 695R mutation was also overrepresented in the general Ashkenazi sample, accounti ng for 12% of the carrier chromosomes, but was only observed on 2 (5%) of 36 Ash kenazi FMF patient chromosomes.. ] According to Pr. Amselem it would most likely be a polymorphism but we would need a serious population study to demonstrate i t and in clinic the answer they have been giving is VUS.
Ambry Genetics RCV000622573 SCV000743064 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768021 SCV000898823 uncertain significance Familial Mediterranean fever; Familial mediterranean fever, autosomal dominant 2020-08-12 criteria provided, single submitter clinical testing MEFV NM_000243.2 exon10 p.Lys695Arg (c.2084A>G): This variant is a well reported but controversial variant in the literature, with several individuals described with features of Familial Mediterranean Fever (FMF) in the homozygous, heterozygous, compound and double heterozygous state, including an entry in GeneReviews (Aksentijevich 1999 PMID:10090880, Feng 2009 PMID:20041150, Attug, 2013 PMID:23981758, Oztuzcu 2014 PMID:24469716, Sediva 2014 PMID:24251727, Shohat 2016 PMID:20301405). This variant is present in 1.6% (422/25790) of European (Finnish) alleles, including 3 homozygotes in the Genome Aggregation Database ( This variant is present in ClinVar, with several discrepant classifications from Pathogenic to Likely Benign (Variation ID:2547). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Of note, at least 1 article in the literature suggests that this variant may have a mild effect or reduced penetrance (Aksentijevich 1999 PMID:10090880), but further information is required for accurate classification. In summary, data on this variant is too unclear for definitive disease classification; therefore, the clinical significance of this variant is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV000002656 SCV000914716 pathogenic Familial Mediterranean fever 2018-09-20 criteria provided, single submitter clinical testing Across a selection of the available literature, the c.2084A>G (p.Lys695Arg) variant has been identified in at least 35 probands with familial Mediterranean fever (FMF) including two in a homozygous state, 14 in a compound heterozygous state, 17 in a heterozygous state, and two asymptomatic relatives (Bernot et al. 1998; Akar et al. 2000; Giaglis et al. 2007; Caglayan et al. 2010; Jarjour RA 2010; Do─ƒan et al. 2012; Moradian et al. 2014; Oztuzcu et al. 2014; Dogan et al. 2015; G├╝ncan et al. 2016; Milenkovi─ç et al. 2016). Due to the presence of asymptomatic relatives that carry p.Lys695Arg, Bernot et al. (1998) suggests the variant demonstrates incomplete penetrance. The p.Lys695Arg variant was absent from 426 control chromosomes and is reported at a frequency of 0.024631 in the Finnish population of the 1000 Genomes Project. Based on the evidence, the p.Lys695Arg variant is classified as pathogenic for familial Mediterranean fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics RCV000002656 SCV001139821 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000213470 SCV001447540 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV001270033 SCV001448751 likely pathogenic Heart, malformation of; Abnormality of cardiovascular system morphology; Renal insufficiency 2016-09-02 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000213470 SCV001450295 pathogenic not provided 2015-08-06 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000002656 SCV001653411 likely pathogenic Familial Mediterranean fever 2021-05-18 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000213470 SCV001712842 uncertain significance not provided 2021-02-03 criteria provided, single submitter clinical testing
OMIM RCV000002656 SCV000022814 pathogenic Familial Mediterranean fever 1998-08-01 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002656 SCV000052842 pathogenic Familial Mediterranean fever 2015-05-20 no assertion criteria provided clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000002656 SCV000115834 not provided Familial Mediterranean fever no assertion provided not provided
GeneReviews RCV000002656 SCV000484971 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415431 SCV000492583 uncertain significance Syncope; Abnormality of the dentition; Intermittent diarrhea; Cachexia; Urticaria (disease); Peripheral neuropathy 2016-05-04 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000213470 SCV001549618 uncertain significance not provided no assertion criteria provided clinical testing The MEFV p.Lys695Arg variant was identified in multiple individuals with familial Mediterranean fever (FMF) or with suspected FMF (Cekin_2017_PMID:28483595; Bernot_1998_PMID:9668175; Debeljak_2015_PMID:26399837; Caglayan_2009_PMID:19934083). However, this variant was also identified in several phenotypically healthy heterozygous individuals (Bernot_1998_PMID:9668175; Milenkovic_2016_PMID:27364639; Debeljak_2015_PMID:26399837; Salehzadeh_2013_PMID:25793047). The variant was identified in dbSNP (ID: rs104895094) and ClinVar (classified as pathogenic by eight submitters including Ambry Genetics, GeneDx, Illumina, and ARUP Laboratories; as likely pathogenic by Counsyl and EGL Genetics; as likely benign by Invitae; and as uncertain significance by Laboratory for Molecular Medicine and four other submitters). The variant was identified in control databases in 1648 of 282878 chromosomes (11 homozygous) at a frequency of 0.005826 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 405 of 25120 chromosomes (freq: 0.01612), Ashkenazi Jewish in 95 of 10370 chromosomes (freq: 0.009161), European (non-Finnish) in 1026 of 129188 chromosomes (freq: 0.007942), Other in 57 of 7224 chromosomes (freq: 0.00789), Latino in 55 of 35440 chromosomes (freq: 0.001552), African in 7 of 24966 chromosomes (freq: 0.00028) and South Asian in 3 of 30616 chromosomes (freq: 0.000098), but was not observed in the East Asian population. The p.Lys695 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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