ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.2177T>C (p.Val726Ala)

gnomAD frequency: 0.00051  dbSNP: rs28940579
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Total submissions: 36
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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 RCV000002649 SCV000052844 pathogenic Familial Mediterranean fever 2022-05-18 criteria provided, single submitter clinical testing Variant summary: MEFV c.2177T>C (p.Val726Ala) results in a non-conservative amino acid change located in the B30.2/SPRY domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 251486 control chromosomes in the gnomAD database, including 9 homozygotes. The variant is reported as one of the most common pathogenic variants in MEFV, and has been reported in numerous affected individuals in the literature. 25 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Eurofins NTD LLC (GA) RCV000220654 SCV000224799 pathogenic not provided 2017-02-15 criteria provided, single submitter clinical testing
GeneDx RCV000220654 SCV000279062 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing In a series of 90 patients of different ethnic groups, V726A accounted for more than 20% of the MEFV pathogenic variants identified (Aksentijevich et al., 1999); Multiple published functional and FMF-knock-in mice studies demonstrate that this variant decreases protein binding activity (Chae et al., 2006) and shows decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo, leading to constitutive activation of the pyrin inflammosome (Park YH et al., 2016); homozygosity for this MEFV variant in knock-in mice produced the most severe inflammation from all tested MEFV variants (Park YH et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28943464, 29080837, 19480334, 11781702, 29393966, 29707173, 29260407, 29326099, 30609409, 28828621, 22975760, 22532615, 22783597, 10090880, 23907647, 9288758, 21995303, 25333069, 23588594, 20669279, 20437121, 20483145, 10879615, 27994174, 27057533, 26400644, 26361084, 27538774, 28483595, 26360812, 18318646, 17408446, 28573371, 29431110, 30826945, 14615741, 11175300, 29543225, 31376265, 30783801, 32199921, 31447099, 32601469, 31589614, 33440462, 11977178, 33144682, 32888943, 10842289, 10852276, 32441320, 10662876, 16785446, 27270401, 19302049, 34549050)
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000220654 SCV000281312 pathogenic not provided 2015-12-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000220654 SCV000604172 pathogenic not provided 2022-01-28 criteria provided, single submitter clinical testing The MEFV c.2177T>C; p.Val726Ala variant (rs28940579) has been published in the literature in individuals with familial Mediterranean fever, juvenile idiopathic arthritis, ankylosing spondylitis, systemic lupus erythematosus and multiple sclerosis with or without another pathogenic variant (Camus 2012, Comack 2013, Cosan 2010, Shinar 2012, Unal 2010). The variant is listed in the ClinVar database (Variation ID: 2540), and is observed in the general population at an overall frequency of 0.19% (551/277208 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. REFERENCES Camus D et al. 'Silent' carriage of two familial Mediterranean fever gene mutations in large families with only a single identified patient. Clin Genet. 2012 Sep;82(3):288-91. PMID: 21995303. Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 Aug;172(8):1061-7. PMID: 23588594. Cosan F et al. Association of familial Mediterranean fever-related MEFV variations with ankylosing spondylitis. Arthritis Rheum. 2010 Nov;62(11):3232-6. PMID: 20669279. Shinar Y et al. Familial Mediterranean FeVer gene (MEFV) mutations as a modifier of systemic lupus erythematosus. Lupus. 2012 Aug;21(9):993-8. PMID: 22532615. Unal A et al. Evaluation of common mutations in the Mediterranean fever gene in Multiple Sclerosis patients: is it a susceptibility gene? J Neurol Sci. 2010 Jul 15;294(1-2):38-42. PMID: 20483145.
Fulgent Genetics,Fulgent Genetics RCV000515437 SCV000611206 pathogenic Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000002649 SCV000629038 pathogenic Familial Mediterranean fever 2021-12-19 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 726 of the MEFV protein (p.Val726Ala). This variant is present in population databases (rs28940579, gnomAD 4%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 9288758, 10879615, 11977178). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish or Middle Eastern ancestry (PMID: 11464238, 15745878, 23907647). ClinVar contains an entry for this variant (Variation ID: 2540). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects MEFV function (PMID: 21600797). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000002649 SCV000711424 likely pathogenic Familial Mediterranean fever 2017-05-25 criteria provided, single submitter clinical testing The p.Val726Ala (NM_000243.2 c.2177T>C) variant in MEFV has been reported in >15 0 homozygous or compound heterozygous individuals with Familial Mediterranean Fe ver and related disorders (Neocleous 2015, Moradian 2010, Moradian 2014, Behesht ian 2016, Neocleous 2016, Coskun 2015, FMF consortium 1997, Oktenli 2010, Unal 2 010, Cosan 2010, Camus 2012, Shinar 2012), often associated with a more mild for m of disease. Additionally, there are >200 individuals with Familial Mediterrane an Fever who are heterozygous for p.Val726Ala and for whom a second MEFV allele has not been identified. This variant has been identified in 0.96% and up to 4.6 % of healthy controls from the matched population from these studies (Moradian 2 014 and Beheshtian 2016) and has been identified in 3.96% (402/10152) of Ashkena zi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad. broadinstitute.org; dbSNP rs28940579). Although this variant is common in specif ic subpopulations, the allele frequency in cases is statistically significantly increased compared to a healthy population suggesting a causative role; in the A rmenian population, the frequency of this variant in healthy individuals was 4.6 0% compared to 27.98% in affected individuals. This variant has also been report ed in ClinVar (Variation ID#2540) as pathogenic by multiple laboratories. Comput ational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In vitro functional studies of the pro tein domain containing p.Val726Ala variant report an impact to protein binding ( Chae 2006). In summary, although the population in specific subpopulations is hi gh, the p.Val726Ala variant is likely pathogenic for autosomal recessive Familia l Mediterranean Fever.
Ambry Genetics RCV000623003 SCV000741066 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000002649 SCV000840008 likely pathogenic Familial Mediterranean fever 2017-07-07 criteria provided, single submitter clinical testing This c.2177T>C (p.Val726Ala) variant in the MEFV gene has been reported in multiple patients with familial Mediterranean fever [OMIM: 608107.0003]. Homozygous patients and compound heterozygous patients for this p.Val726Ala variant present with fever, abdominal pain and thoracic pain [PMID 23907647]. This variant has been detected in 224 heterozygous and 6 homozygous individuals from the ExAC population database (http://exac.broadinstitute.org/variant/16-3293310-A-G); no phenotypic information is available for the homozygous individuals. Valine at amino acid position 726 of the MEFV protein is not well conserved in mammals and computer-based algorithms predict this p.Val726Ala change to be benign. Thus, this variant is classified as likely pathogenic. Apparent homozygosity of this variant may be caused by the presence of the mutant allele on both chromosomes of this individual, or the presence of a mutant allele on one allele and an exonic deletion on the opposite allele. Segregation analysis such as parental study is recommended to resolve the apparent homozygosity of this variant in this individual.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000515437 SCV000898822 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.Val726Ala (c.2177T>C): This variant is a well established, common pathogenic variant for Familial Mediterranean Fever. This variant has been reported in several publications, including a Genereviews entry describing this variant as disease causing (International FMF Consortium 1997 PMID:8288758, Moradian 2014 PMID:23907647, Shothat 2016 PMID:20301405). This variant is present in 4% (407/10368) of Ashkenazi Jewish alleles including 8 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3293310-A-G?dataset=gnomad_r2_1). 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:2540). In summary, this variant is classified as pathogenic based on the data above.
Illumina Laboratory Services,Illumina RCV000002649 SCV000914715 pathogenic Familial Mediterranean fever 2018-09-24 criteria provided, single submitter clinical testing The MEFV c.2177T>C (p.Val726Ala) variant is one of the most common pathogenic variants known to cause familial Mediterranean fever (FMF) and is well-documented in the literature. Across a selection of available literature, the p.Val726Ala variant has been identified in at least 110 probands in a homozygous state and 21 probands in a compound heterozygous state (International FMF Consortium, 1997; Mattit et al. 2006; Bektas et al. 2008; Moradian et al. 2014). The frequency of the p.Val726Ala variant is significantly higher in FMF probands than in controls, and has been reported in 14-28% of proband alleles and 2.3-4.6% of control alleles in two studies (Mattit et al. 2006; Moradian et al. 2014). The p.Val726Ala variant is reported at a frequency of 0.004021 in the Other population of the Genome Aggregation Database. Based on the evidence, the p.Val726Ala 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.
CeGaT Center for Human Genetics Tuebingen RCV000220654 SCV001150750 pathogenic not provided 2022-06-01 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000002649 SCV001194192 pathogenic Familial Mediterranean fever 2019-10-18 criteria provided, single submitter clinical testing NM_000243.2(MEFV):c.2177T>C(V726A) is classified as pathogenic in the context of familial Mediterranean fever. Please note that 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 10234504, 9288758, 10612841, 16378925, 21995303, 23907647, 16785446, 10024914, 10364520, 16378925. Classification of NM_000243.2(MEFV):c.2177T>C(V726A) 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.
Hadassah Hebrew University Medical Center RCV000002649 SCV001437666 pathogenic Familial Mediterranean fever 2019-06-20 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center,Al Jalila Childrens Speciality Hospital RCV000515437 SCV001448262 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 RCV000220654 SCV001449579 pathogenic not provided 2014-10-01 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000002649 SCV001469021 pathogenic Familial Mediterranean fever 2021-01-07 criteria provided, single submitter clinical testing MEFV c.2177T>C is one of the most common variants associated with autosomal recessive FMF and it has been identified in many affected individuals in the homozygous and compound heterozygous states. This MEFV variant (rs28940579) has been reported in ClinVar and is present in a large population dataset (gnomAD: 561/282870 total alleles; 0.198%; 9 homozygotes). There is evidence that p.Val726Ala leads to decreased binding of the B30.2 domain of human pyrin to caspase-13 in vitro. We consider c.2177T>C to be pathogenic.
New York Genome Center RCV000984975 SCV001622928 pathogenic Familial Mediterranean fever, autosomal dominant 2020-07-09 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories,Mayo Clinic RCV000220654 SCV001714542 pathogenic not provided 2021-03-12 criteria provided, single submitter clinical testing PS3, PS4, PM3
Fulgent Genetics,Fulgent Genetics RCV001535867 SCV001752485 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 RCV000002649 SCV001810499 pathogenic Familial Mediterranean fever 2021-07-22 criteria provided, single submitter clinical testing
3billion RCV000002649 SCV002318773 pathogenic Familial Mediterranean fever 2022-03-22 criteria provided, single submitter clinical testing 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: 9288758, 10879615) and co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 11977178). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21600797). A missense variant is a common mechanism associated with Familial Mediterranean fever, AR. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0022232). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Mendelics RCV000984975 SCV002517610 pathogenic Familial Mediterranean fever, autosomal dominant 2022-05-04 criteria provided, single submitter clinical testing
Department of Human Genetics,Hannover Medical School RCV000984975 SCV002525497 pathogenic Familial Mediterranean fever, autosomal dominant 2022-06-09 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002262541 SCV002543739 pathogenic Autoinflammatory syndrome 2022-04-19 criteria provided, single submitter clinical testing
OMIM RCV000002649 SCV000022807 pathogenic Familial Mediterranean fever 1997-09-01 no assertion criteria provided literature only
GeneReviews RCV000002649 SCV000484972 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000984975 SCV001132897 pathogenic Familial Mediterranean fever, autosomal dominant 2019-08-25 no assertion criteria provided clinical testing
Reproductive Health Research and Development,BGI Genomics RCV000002649 SCV001142454 pathogenic Familial Mediterranean fever 2020-01-06 no assertion criteria provided curation NM_000243.2:c.2177T>C in the MEFV gene has an allele frequency of 0.039 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies demonstrate that p.Val726Ala has decreased protein binding activity(PMID: 16785446). It was detected in multiple individuals with autosomal recessive Familial Mediterranean Fever, compound heterozygous with c.2080A>G (p.Met694Val)(PMID: 10879615),c.2080A>G (p.Met694Val) (PMID: 11977178). The patient's phenotype is highly specific for MEFV gene (PMID: 10879615; 11977178).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PM3_Strong; PS3; PP4.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000220654 SCV001744379 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000220654 SCV001932036 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000220654 SCV001959385 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000220654 SCV001969445 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000220654 SCV002022780 likely pathogenic not provided 2021-10-01 no assertion criteria provided clinical testing
Natera, Inc. RCV000002649 SCV002093878 pathogenic Familial Mediterranean fever 2020-01-21 no assertion criteria provided clinical testing

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