ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.2040G>A (rs28940580)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000216518 SCV000279055 pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing The M680I variant accounts for approximately 9% of identifiable MEFV pathogenic variants and has been detected in individuals from multiple ethnic backgrounds (Aksentijevich et al., 1999; Moradian et al., 2014). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. M680I is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. Different nucleotide changes also leading to M680I (c.2040G>C, c.2040G>T), a missense variant at the same codon (M680L), and missense variants in nearby residues (S675N, G678E, T681I) 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. Furthermore, functional studies of the M680I have shown that it results in reduced binding activity of the protein (Chae et al., 2006). Therefore, we interpret M680I as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999743 SCV000604195 pathogenic not specified 2019-05-21 criteria provided, single submitter clinical testing The MEFV c.2040G>A; p.Met680Ile variant (rs28940580) is reported in the literature in families affected with familial Mediterranean fever (FMF) (Moradian 2014, Procopio 2018), and segregates with disease when in-trans with another pathogenic variant (Aksentijevich 1999). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2550), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon resulting in the same amino acid alteration (c.2040G>C; p.Met680Ile) is a common pathogenic variant in FMF (Moradian 2014, Procopio 2018). Based on available information, this variant is considered to be pathogenic. References: Aksentijevich I et al. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet. 1999; 64(4):949-62. Moradian MM et al. Patient management and the association of less common familial Mediterranean fever symptoms with other disorders. Genet Med. 2014 Mar;16(3):258-63. Procopio V et al. Genotype-phenotype correlation in FMF patients: A non classic" recessive autosomal or "atypical" dominant autosomal inheritance? Gene. 2018 Jan 30;641:279-286."
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002659 SCV000696061 pathogenic Familial Mediterranean fever 2019-12-04 criteria provided, single submitter clinical testing Variant summary: MEFV c.2040G>A (p.Met680Ile) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251474 control chromosomes (gnomAD). c.2040G>A has been reported in the literature in multiple individuals affected with Familial Mediterranean Fever (e.g. Akin_2010, Aksentijevich_1999). A different variant causing the same amino acid change (i.e. c.2040G>C, p.Met680Ile) is considered one of the most frequently observed MEFV mutations. Collectively, M680I without specifying nucleotide change, has been reported in multiple individuals affected with Familial Mediterranean Fever (e.g. Kriegshauser_2018, Yilmaz_2009). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Furthermore, in 2018 the experts international study group for systemic autoinflammatory diseases (INSAID) decided a consensus classification of pathogenic for the variant (Van Gijn_2018). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000002659 SCV000826534 pathogenic Familial Mediterranean fever 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 680 of the MEFV protein (p.Met680Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs28940580, ExAC 0.003%). This variant has been reported in several individuals and families affected with familial Mediterranean fever (PMID: 23907647, 10090880, 11977178, 29080837). ClinVar contains an entry for this variant (Variation ID: 2550). Experimental studies using a knock-in mouse model have shown that this missense change is sufficient to induce a phenotype consistent with familial Mediterranean fever (PMID: 21600797). A different variant (c.2040G>C) giving rise to the same protein effect observed here (p.Met680Ile) has been reported in individuals affected with familial Mediterranean fever (PMID: 23907647, 9288758) and Behcet's disease (PMID: 23973724, 21623663), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000002659 SCV000914717 pathogenic Familial Mediterranean fever 2018-10-26 criteria provided, single submitter clinical testing The MEFV c.2040G>A (p.Met680Ile) variant has been reported in at least four studies in which it is found in a total of eight probands including one in a homozygous state, five in a compound heterozygous state and two in a heterozygous state (Aksentijevich et al. 1999; Sahin et al. 2008; Sabbagh et al. 2008; Jarjour et al. 2010). The variant was absent from 447 control chromosomes and is reported at a frequency of 0.000215 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies demonstrate that the variant results in decreased binding of caspase-1 compared to wild type (Chae et al. 2006). Another variant at the same nucleotide position (c.2040G>C) that results in the same amino acid change has been frequently reported in the literature as pathogenic. The p.Met680Ile variant has been reported in additional studies in which the cDNA change has not been specified. In at least 13 studies the p.Met680Ile variant has been found in a homozygous state in at least 81 probands, in a compound heterozygous state in at least 159 probands, in a heterozygous state in at least 88 individuals and in nine of 431 controls (Cazeneuve et al. 1999; Shinawi et al. 2000; Akar et al. 2000; Yilmaz et al. 2001; Gershoni-Baruch et al. 2002; Etem et al. 2010; Talaat et al. 2012; Ocak et al. 2013; Moradian et al. 2014; Salehzadeh et al. 2015a; Salehzadeh et al. 2015b; Kilic et al. 2015; Salah et al. 2016). Based on the collective evidence, the p.Met680Ile 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000216518 SCV001134278 pathogenic not provided 2019-02-20 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a tolerated effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Mendelics RCV000002659 SCV001139831 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000216518 SCV001245672 pathogenic not provided 2020-05-01 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center,Al Jalila Childrens Speciality Hospital RCV001269325 SCV001448265 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 RCV000216518 SCV001450258 pathogenic not provided 2014-12-02 criteria provided, single submitter clinical testing
OMIM RCV000002659 SCV000022817 pathogenic Familial Mediterranean fever 1999-04-01 no assertion criteria provided literature only
Counsyl RCV000002659 SCV001132427 pathogenic Familial Mediterranean fever 2019-03-15 no assertion criteria provided clinical testing
Natera, Inc. RCV000002659 SCV001462100 pathogenic Familial Mediterranean fever 2020-09-16 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV001283820 SCV001469229 pathogenic Familial mediterranean fever, autosomal dominant 2020-06-07 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000216518 SCV001550238 pathogenic not provided no assertion criteria provided clinical testing The MEFV p.Met680Ile (c.2040G>A) variant was identified in 1 of 548 proband chromosomes (frequency: 0.0018) from individuals with Familial Mediterranean fever (FMF) (Aksentijevich_1999_PMID:10090880). The variant was also identified in dbSNP (ID: rs28940580), LOVD 3.0 and ClinVar (classified as pathogenic for FMF by GeneDx, ARUP Laboratories, Integrated Genetics, Invitae and Illumina). The variant was identified in control databases in 2 of 251474 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 2 of 113758 chromosomes (freq: 0.000018), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. Another variant in the MEFV gene, c.2040G>C, causes the same M680I missense change, and is a common variant associated with FMF (ClinVar ID: 36507). The M680I change was identified in 48/514 Turkish patients with FMF (freq=0.048; 20 heterozygotes, 27 compound heterozygotes, 1 homozygote), however the cDNA change causing this missense change (c.2040G>A or c.2040G>C) was not reported (Cekin_2017_PMID: 28483595). Although four out of five computational analyses (PolyPhen-2, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein, the p.Met680 residue is conserved across mammals and other organisms. Further, functional studies of the M680I variant have demonstrated abnormal pyrin protein function (encoded by MEFV) as well as an FMF phenotype in M680I knock-in mice (Chae_2006_PMID: 16785446; Chae_2011_PMID: 21600797). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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