16-3243310-A-G

Position:

• chr16-3243310-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The ENST00000219596.6(MEFV):​c.2177T>C​(p.Val726Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,072 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V726D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (23 hom.)
• Consequence: MEFV ENST00000219596.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:50 O:2
• Conservation: PhyloP100: -0.165

Genes affected

MEFV (HGNC:6998): (MEFV innate immunity regulator, pyrin) This gene encodes a protein, also known as pyrin or marenostrin, that is an important modulator of innate immunity. Mutations in this gene are associated with Mediterranean fever, a hereditary periodic fever syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 16-3243310-A-G is Pathogenic according to our data. Variant chr16-3243310-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3243310-A-G is described in Lovd as [Pathogenic]. Variant chr16-3243310-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.09626025). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEFV	NM_000243.3	c.2177T>C	p.Val726Ala	missense_variant	10/10	ENST00000219596.6	NP_000234.1
MEFV	NM_001198536.2	c.*381T>C		3_prime_UTR_variant	9/9		NP_001185465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEFV	ENST00000219596.6	c.2177T>C	p.Val726Ala	missense_variant	10/10	1	NM_000243.3	ENSP00000219596	P3

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152066 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00217 AC: 545 AN: 251486 Hom.: 9 AF XY: 0.00190 AC XY: 258 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000932

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00130 AC: 1896 AN: 1461888 Hom.: 23 Cov.: 32 AF XY: 0.00132 AC XY: 963 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000469

Gnomad4 OTH exome AF: 0.00435

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152184 Hom.: 3 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74384

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000721

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00280 Hom.: 11

Bravo AF: 0.00154

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00185 AC: 224

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00160

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:50 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial Mediterranean fever Pathogenic:23 Other:1

Pathogenic, no assertion criteria provided	research	Genomics And Bioinformatics Analysis Resource, Columbia University	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 07, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 18, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 24, 2018	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 07, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 11, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	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 -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -

not provided Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 22, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2021	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MEFV: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting, BP4 -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 15, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 01, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 23, 2024	PM3, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 19, 2024	- -

Familial Mediterranean fever, autosomal dominant Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Jun 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -

Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	May 03, 2021	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. -

Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

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. -

Autoinflammatory syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 19, 2022

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MEFV-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.17
DANN	Benign	0.24
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-2.2	N;.;.
MutationTaster	Benign	2.2e-11	A;A;A;A
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.9	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.26
MVP		0.53
MPC		0.14
ClinPred		0.023	T
GERP RS		-0.52
Varity_R		0.089
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28940579; hg19: chr16-3293310;