ClinVar Genomic variation as it relates to human health

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)

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.

PM3, PS3, PS4

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.

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.

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.

MEFV: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting, BP4

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.

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.

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.