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rs28940579

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PP5_Very_StrongBP4BS2

The NM_000243.3(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. 14/20 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
NM_000243.3 missense

Scores

1
18

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:43O:2

Conservation

PhyloP100: -0.165
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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.
BS2
High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MEFVNM_000243.3 linkuse as main transcriptc.2177T>C p.Val726Ala missense_variant 10/10 ENST00000219596.6
MEFVNM_001198536.2 linkuse as main transcriptc.*381T>C 3_prime_UTR_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MEFVENST00000219596.6 linkuse as main transcriptc.2177T>C p.Val726Ala missense_variant 10/101 NM_000243.3 P3O15553-2

Frequencies

GnomAD3 genomes
AF:
0.00144
AC:
219
AN:
152066
Hom.:
3
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:43Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial Mediterranean fever Pathogenic:18Other:1
Pathogenic, criteria provided, single submitterclinical testingArcensusFeb 01, 2013- -
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 1997- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterAug 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaSep 24, 2018The 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. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityJan 07, 2021MEFV 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. -
Likely pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineJul 07, 2017This 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 submitterclinical testingInvitaeJan 31, 2024This 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. -
Pathogenic, criteria provided, single submitterclinical testing3billionMar 22, 2022The 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 submitterclinical testingIntergen, Intergen Genetics and Rare Diseases Diagnosis Center-- -
Pathogenic, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 02, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 25, 2017The 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. -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Jan 21, 2020- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 18, 2022Variant 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, no assertion criteria providedresearchGenomics And Bioinformatics Analysis Resource, Columbia University-- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Pathogenic, criteria provided, single submitterclinical testingHadassah Hebrew University Medical CenterJun 20, 2019- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 18, 2019NM_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 providedcurationReproductive Health Research and Development, BGI GenomicsJan 06, 2020NM_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. -
not provided Pathogenic:13
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsDec 22, 2015- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 14, 2023PM3, PS3, PS4 -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalOct 01, 2014- -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 27, 2023- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023The 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 submitterclinical testingEurofins Ntd Llc (ga)Feb 15, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 03, 2021In 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 providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024MEFV: PM3:Very Strong, PM2:Supporting, PP1, PP4, PS3:Supporting, BP4 -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Familial Mediterranean fever, autosomal dominant Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingDepartment of Human Genetics, Hannover Medical SchoolJun 09, 2022- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 31, 2023- -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterJul 09, 2020- -
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityAug 25, 2019- -
Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:3Other:1
not provided, no classification providedphenotyping onlyGenomeConnect - 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 submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMay 03, 2021MEFV 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. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 18, 2017- -
Pathogenic, criteria provided, single submitterclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalOct 04, 2020- -
Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021MEFV 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. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJun 30, 2021- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 10, 2022The 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 the available evidence, the c.2177T>C (p.V726A) alteration is classified as pathogenic for autosomal recessive FMF; however, its clinical significance for autosomal dominant FMF is unclear. 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). The proband is reported to be of Ashkenazi Jewish ancestry. This amino acid position is poorly conserved in available vertebrate species, and alanine is the reference amino acid in other 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 submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenApr 19, 2022- -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28940579; hg19: chr16-3293310; API