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

gnomAD frequency: 0.00147  dbSNP: rs28940579

Total submissions: 52

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	2023-11-29	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% (561/282870 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. Pathogenic MEFV variants are causative for familial Mediterranean fever (MIM: 608107). 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 82(3):288-91. PMID: 21995303. Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 172(8):1061-7. PMID: 23588594. Cosan F et al. Association of familial Mediterranean fever-related MEFV variations with ankylosing spondylitis. Arthritis Rheum. 2010 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 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 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002649	SCV000629038	pathogenic	Familial Mediterranean fever	2024-01-31	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%), and has an allele count higher than expected for a pathogenic variant. 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". 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	2022-06-23	criteria provided, single submitter	clinical testing	The p.Val726Ala (NM_000243.2 c.2177T>C) variant in MEFV has been reported in >150 homozygous or compound heterozygous individuals with Familial Mediterranean Fever and related disorders (Neocleous 2015 PMID: 25393764, Moradian 2010 PMID: 20485448, Moradian 2014 PMID: 23907647, Beheshtian 2016 PMID: 27659338, Neocleous 2016 PMID: 27994174, Coşkun 2015 PMID: 26690517, FMF consortium 1997 PMID: 9288094, Unal 2010 PMID: 20483145, Cosan 2010 PMID: 20669279, Camus 2012 PMID: 21995303, Shinar 2012 PMID: 22532615), often associated with a more mild form of disease. Additionally, there are >200 individuals with Familial Mediterranean 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 2014 PMID: 23907647, Beheshtian 2016 PMID: 27659338) and has been identified in 3.96% (402/10152) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28940579). Although this variant is common in specific subpopulations, the allele frequency in cases is statistically significantly increased compared to a healthy population suggesting a causative role; in the Armenian population, the frequency of this variant in healthy individuals was 4.60% compared to 27.98% in affected individuals. This variant has also been reported in ClinVar (Variation ID#2540) as pathogenic by multiple laboratories. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In vitro functional studies of the protein domain containing p.Val726Ala variant report an impact to protein binding (Chae 2006 PMID: 21600797). In summary, although the population in specific subpopulations is high, the p.Val726Ala variant is pathogenic for autosomal recessive Familial Mediterranean Fever. ACMG/AMP Criteria applied: PM3_VeryStrong, PS4, PS3_Supporting.
Ambry Genetics	RCV000623003	SCV000741066	pathogenic	Inborn genetic diseases	2023-09-22	criteria provided, single submitter	clinical testing	The c.2177T>C (p.V726A) alteration is located in exon 10 of the MEFV gene. This alteration results from a T to C substitution at nucleotide position 2177, causing the valine (V) at amino acid position 726 to be replaced by an alanine (A). Based on data from gnomAD, the C allele has an overall frequency of 0.2% (561/282870) total alleles studied. The highest observed frequency was 3.93% (407/10368) of Ashkenazi Jewish alleles. This alteration is considered to be one of five common founder mutations in a number of ethnic populations, including Ashkenazi Jewish, and is associated with a milder familial Mediterranean fever (FMF) phenotype (Touitou, 2001). This alteration has been seen in FMF patients both in heterozygous form and in combination with a second MEFV alteration (Moradian, 2010). This amino acid position is poorly conserved in available vertebrate species. The p.V726 amino acid is located in the PRYSPRY domain of the pyrin protein, which is a globular domain with a binding cavity. 3-D modeling showed that V726 is located on a loop further away from the binding cavity in the lower part of the PRYSPRY domain, and altering it may affect either interaction with other molecules or the folding of this part of the domain (Goulielmos, 2006). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
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	2024-07-01	criteria provided, single submitter	clinical testing	MEFV: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting, BP4
Myriad Genetics, 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 and Genomics, 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	2023-02-14	criteria provided, single submitter	clinical testing	PM3, PS3, PS4
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
Revvity Omics, Revvity	RCV000220654	SCV002022780	likely pathogenic	not provided	2023-11-27	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
Arcensus	RCV000002649	SCV002564575	pathogenic	Familial Mediterranean fever	2013-02-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000002649	SCV002581659	pathogenic	Familial Mediterranean fever	2022-08-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001535867	SCV003920191	pathogenic	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant; Acute febrile neutrophilic dermatosis	2021-03-30	criteria provided, single submitter	clinical testing	MEFV NM_000243 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% (402/10152) of Ashkenazi Jewish alleles including 9 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rsrs28940579). 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.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000002649	SCV003922394	pathogenic	Familial Mediterranean fever		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000984975	SCV004194402	pathogenic	Familial Mediterranean fever, autosomal dominant	2024-03-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000220654	SCV004242670	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000002649	SCV004809661	likely pathogenic	Familial Mediterranean fever	2024-04-04	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000002649	SCV004812461	pathogenic	Familial Mediterranean fever	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change in MEFV is predicted to replace valine with alanine at codon 726, p.(Val726Ala). The valine residue is weakly /conserved (11/97 vertebrates, UCSC), and is located in the SPRY domain. There is a moderate physicochemical difference between valine and alanine. The highest population minor allele frequency in the population database gnomAD v2.1 is 3.9% (407/10,368 alleles, 8 homozygotes) in the Ashkenazi Jewish population, while the highest continental population frequency is 0.09% (115/129,180 alleles, 1 homozygote) in the European (non-Finnish) population. This is the third most commonly occurring variant reported in familial Mediterranean fever (FMF) cases (PMID: 36076017). It has been identified in individuals with FMF in the homozygous state and compound heterozygous with a second pathogenic variant, and segregates with disease in multiple families (PMID: 11977178, 21995303, 34988684). However, the variant is also commonly detected as a single heterozygous variant when autosomal recessive inheritance is expected suggesting missing heritability (PMID: 20301405). A homozygous FMF-knock-in mouse model of the variant induces spontaneous inflammation that is similar to or more severe that the inflammation observed in FMF patients (PMID: 21600797). Multiple lines of computational evidence predict a benign effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, BP4.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000002649	SCV005038674	pathogenic	Familial Mediterranean fever		criteria provided, single submitter	not provided
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000002649	SCV005051858	pathogenic	Familial Mediterranean fever	2024-02-01	criteria provided, single submitter	curation
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000220654	SCV005198749	pathogenic	not provided	2024-02-19	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000002649	SCV005398586	pathogenic	Familial Mediterranean fever	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with familial Mediterranean fever (FMF; MIM#134610, MIM# 249100). Gain of function is a mechanism demonstrated by mouse models (PMID: 21600797). However, there has been some controversy as to whether this is due to a loss of an inhibitor or gain of pro-inflammatory function (PMID: 31088470). (I) 0108 - This gene is associated with both recessive and dominant disease. FMF is mostly autosomal recessive, however approximately 31% of patients with clinical FMF lack a second disease-associated variant (PMID: 29393966, PMID: 31088470). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been reported for variants in this gene (PMID: 11528510, PMID: 29393966). Penetrance for autosomal dominant FMF is incomplete, and the clinical severity is less than in autosomal recessive FMF (PMID: 20301405). (I) 0115 - Variants in this gene are known to have variable expressivity. There is variability of clinical symptoms in patients carrying the same mutations, even within the same family (PMID: 29393966). Previous studies have identified significant effects of modifying genes and environmental factors on the clinical phenotypes (PMID: 31088470). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to alanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (543 heterozygotes and 9 homozygotes, including 391 heterozygotes and 8 homozygotes from the Ashkenazi-Jewish population). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated SPRY domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most common variants causing familial Mediterranean fever, and is considered to be a founder variant in the Ashkenazi Jewish population. It has been reported as homozygous and compound heterozygous in FMF patients, and as heterozygous in FMF patients without a second disease-associated MEFV variant. This variant has also been associated with reduced penetrance and variable expressivity (ClinVar, PMID: 11528510, PMID: 29393966). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In transfected cells, the mutant protein had decreased binding to caspase-1 (PMID: 16785446). This is consistent with the functional study using knock-in mice which showed gain of caspase-1 activation (PMID: 21600797). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000002649	SCV000022807	pathogenic	Familial Mediterranean fever	1997-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000002649	SCV000484972	not provided	Familial Mediterranean fever		no assertion 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
Natera, Inc.	RCV000002649	SCV002093878	pathogenic	Familial Mediterranean fever	2020-01-21	no assertion criteria provided	clinical testing
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000002649	SCV004024083	pathogenic	Familial Mediterranean fever		no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV000515437	SCV004037571	not provided	Familial Mediterranean fever; Familial Mediterranean fever, autosomal dominant		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 08-18-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000002649	SCV004101056	pathogenic	Familial Mediterranean fever	2023-11-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739280	SCV005366093	pathogenic	MEFV-related disorder	2024-05-29	no assertion criteria provided	clinical testing	The MEFV c.2177T>C variant is predicted to result in the amino acid substitution p.Val726Ala. This variant has been reported in the homozygous and compound heterozygous states in numerous individuals with familial Mediterranean fever and is considered a founder variant in multiple populations, including the Ashkenazi Jewish population (see, for example, International FMF Consortium 1997. PubMed ID: 9288758; Gershoni-Baruch et al. 2001. PubMed ID: 11528510; Moradian et al. 2014. PubMed ID: 23907647). This variant has been noted to be associated with a milder phenotype (Cekin et al. 2017. PubMed ID: 28483595). In vivo and in vitro experimental studies suggest this variant impacts protein function (Chae et al. 2011. PubMed ID: 21600797; Honda et al. 2021. PubMed ID: 33733382). This variant is reported in 3.9% of alleles in individuals of Ashkenazi Jewish descent in a large population database. This variant is interpreted as pathogenic.