16-3243407-T-C
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM5PP5_Very_StrongBP4
The NM_000243.3(MEFV):c.2080A>G(p.Met694Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,614,154 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. M694I) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 3 hom. )
Consequence
MEFV
NM_000243.3 missense
NM_000243.3 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 0.527
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
In a strand (size 7) in uniprot entity MEFV_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000243.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-3243405-C-T is described in Lovd as [Pathogenic].
PP5
Variant 16-3243407-T-C is Pathogenic according to our data. Variant chr16-3243407-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3243407-T-C is described in Lovd as [Pathogenic]. Variant chr16-3243407-T-C is described in Lovd as [Likely_pathogenic]. Variant chr16-3243407-T-C is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.04752019). . 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.2080A>G | p.Met694Val | missense_variant | 10/10 | ENST00000219596.6 | NP_000234.1 | |
| MEFV | NM_001198536.2 | c.*284A>G | 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.2080A>G | p.Met694Val | missense_variant | 10/10 | 1 | NM_000243.3 | ENSP00000219596 | P3 |
Frequencies
GnomAD3 genomes 0.000131 AC: 20AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000282 AC: 71AN: 251478Hom.: 1 AF XY: 0.000294 AC XY: 40AN XY: 135918
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:51Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:16
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 14, 2022 | PP5, PM1, PS3, PS4_moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jul 28, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | MEFV: PP1:Strong, PM1, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, BP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Nov 24, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 15, 2020 | Reported as the most common pathogenic variant associated with familial Mediterranean fever, especially in Turkish, Armenian, Arab, and Jewish populations (Ozen, 2017; Askentijevich et al., 1999); Individuals who are homozygous for M694V are at higher risk for earlier onset, more severe symptoms, and for developing amyloidosis (Ozen, 2017); Multiple published functional and FMF-knock-in mice studies demonstrated the damaging effect of the M694V variant, e.g., showing loss of suppression of IL-8 secretion in vitro (Sugiyama et al., 2014) and decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo (Park, 2016); Other missense variants altering the same residue (M694I/K/L) and nearby residues (e.g., K695R/M) have been reported in the Human Gene Mutation Database in association with FMF (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 21557533, 27538774, 27270401, 28800602, 28828621, 24369413, 11728994, 20669279, 11005788, 21483284, 23832993, 21995303, 21360101, 21329287, 22960328, 23588594, 22037353, 22975760, 24123366, 20437121, 25036284, 22790142, 20008920, 20483145, 22532615, 11470495, 10667038, 22487161, 23633568, 22783597, 19151978, 21259007, 23334425, 20049453, 20828792, 10879615, 21623663, 21228398, 10090880, 24251727, 23907647, 24533546, 26400644, 24318677, 9288758, 27994174, 27766107, 27621632, 27659338, 14636645, 15711787, 25550179, 12189462, 26071026, 26510601, 16721494, 18183427, 26360812, 18318646, 16179998, 17111701, 28573371, 11781702, 19151977, 28386255, 16523434, 17949559, 18408398, 9781020, 11175300, 14615741, 30826945, 30946743, 29543225, 30009667, 31814694, 30783801, 29027576, 30171907, 32199921, 32601469, 31589614, 33440462, 11977178, 30755392, 32888943, 29080837, 10852276, 10662876) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 19, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MEFV p.Met694Val variant is the most common variant associated with Familial Mediterranean fever (FMF), and has been identified in 1598 of 3112 proband chromosomes (frequency: 0.513) from patients with FMF (Yilmaz_2001_PMID:11464248; Tunca_2005_PMID:15643295; Domingo_2000_PMID:10854105). The variant was also identified in dbSNP (ID: rs61752717), ClinVar (classified as pathogenic by Invitae, GeneDx and nine other laboratories, and as likely pathogenic by the Swiss Institute of Bioinformatics) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 77 of 282876 chromosomes (1 homozygous) at a frequency of 0.000272 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 7 of 7226 chromosomes (freq: 0.000969), European (non-Finnish) in 59 of 129184 chromosomes (freq: 0.000457), Latino in 9 of 35438 chromosomes (freq: 0.000254) and African in 2 of 24968 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. One study of a Turkish population with FMF found that homozygosity for the M694V variant was associated with an earlier age of onset and a higher likelihood or developing arthritis and arthralgia (Tunca_2005_PMID:15643295). Individuals with the p.M694V pathogenic variant, particularly homozygous individuals, are at increased risk for amyloidosis (Dusunsel_2008_PMID:18353061) and have a decreased response to colchicine (Soylemezoglu_2010_PMID:20008920). Another study found that the M694V variant was associated with increased susceptibility to ankylosing spondylitis (OR=3.33) (Zhong_2017_PMID:28800602). The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (MaxEntScan, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity.The p.Met694 residue is not conserved in mammals and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Further, functional studies of the M694V variant have shown impaired pyrin (encoded by the MEFV gene) function (Sugiyama_2014_PMID:24318677). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 03, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Jun 20, 2023 | PS4, PS3, PM3 - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | The MEFV c.2080A>G;p.Met694Val variant (rs61752717) has been published as a common familial Mediterranean fever (FMF) pathogenic variant (The International FMF Consortium 1997, Touitou 2001). Functional analysis of the variant protein shows diminished capacity to suppress IL-8 secretion in synovial cell cultures (Sugiyama 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2538), and is seen in the general population at an overall frequency of 0.03% (77/282876 including 1 homozygote) in the Genome Aggregation Database. Additionally, another variant at this codon (Met694Ile) has been reported in individuals with FMF and is considered pathogenic (Sugiyama 2014). Based on the above information, this variant is considered pathogenic. References: The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. 1997 Cell. 90:797-807. PMID: 9288758. Sugiyama R et al. Defect of suppression of inflammasome-independent interleukin-8 secretion from SW982 synovial sarcoma cells by familial Mediterranean fever-derived pyrin mutations. Mol Biol Rep. 2014 Jan;41(1):545-53. PMID: 24318677. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001 9(7):478-483. PMID: 11464238. - |
Familial Mediterranean fever Pathogenic:14Other:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 694 of the MEFV protein (p.Met694Val). This variant is present in population databases (rs61752717, gnomAD 0.04%). This missense change has been observed in individual(s) with familial Mediterranean fever (FMF) and in the homozygous state this variant is associated with a higher rate of amyloidosis and a lower response to colchicine (PMID: 9781020, 10364520, 20008920, 21290976, 22037353). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2538). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects MEFV function (PMID: 24318677). This variant disrupts the p.Met694 amino acid residue in MEFV. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10787449, 15942916, 24318677). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2010 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Pathogenic and reported on 06-02-2016 by Lab or GTR ID 506013. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Hadassah Hebrew University Medical Center | Jun 20, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 27, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 20, 2023 | Criteria applied: PS3,PS4,PM5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | NM_000243.2(MEFV):c.2080A>G(M694V, aka MED) is classified as pathogenic in the context of familial Mediterranean fever. 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 10364520, 11464248, 23907647, 23334425, 16785446. Classification of NM_000243.2(MEFV):c.2080A>G(M694V) 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, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.027%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21600797). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.41; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002538). 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: 10879615, 9288758). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 11977178). A different missense change at the same codon (p.Met694Ile) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002539). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Likely Pathogenic, for Familial mediterranean fever, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PS3 => Well-established functional studies show a deleterious effect (PMID:24318677). PM2 => Present in Exome Aggregation Consortium with allele frequency compatible with disease prevalence. According to Genetics Home Reference (https://ghr.nlm.nih.gov/condition/familial-mediterranean-fever), Familial Mediterranean fever primarily affects populations originating in the Mediterranean region, particularly people of Armenian, Arab, Turkish, or Jewish ancestry. The disorder affects 1 in 200 to 1,000 people in these populations. It is less common in other populations. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed missense variant c.2080A>G (p.Met694Val) in MEFV gene has been reported previously in multiple individuals in both homozygous and compound heterozygous state in individuals affected with familial mediterranean fever (Grossman et al. 2018). Functional studies of this variant have shown impaired pyrin (encoded by the MEFV gene) function (Sugiyama et al. 2014). Exon 10 is a hotspot region for variants in MEFV gene causing familial mediterranean fever (Grossman et al. 2018). The p.Met694Val variant is present with an allele frequency of 0.03% (71 heterozygotes; 1 homozygote) in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Met694Val in MEFV is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 694 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 2022 | The p.Met694Val variant in MEFV is the most common cause of familial Mediterranean fever (FMF) in Israel, Armenia and Turkey, and it is also present in other populations (Dewalle 1998 PMID: 9781020, Cazeneuve 1999 PMID: 10364520, Bathelier 2010 PMID: 21290976, Akpolat 2012 PMID: 22037353). In the homozygous state this variant is associated with a higher rate of amyloidosis and a lower response to colchicine (Soylemezoglu 2010 PMID: 20008920, Akpolat 2012 PMID: 22037353). It has also been reported in ClinVar (Variation ID 2385). It has been identified in 12/68010 European chromosomes by gnomAD. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, in vitro functional studies show decreased capacity of the variant protein to suppress IL-8 secretion in synovial cell cultures and FMF-knock-in mice studies showed decreased binding of PKN1 and 14-3-3 protein to murine pyrin in vivo, thereby providing some evidence that this variant impacts protein function (Sugiyama 2014 PMID: 24318677, Park 2016 PMID: 27270401). Additionally, another variant involving this codon (p.Met694Ile) has been reported in individuals with FMF and is classified as pathogenic by several clinical laboratories in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive FMF. ACMG/AMP Criteria applied: PS3_Moderate, PM3_VeryStrong, PM2_Supporting, PP1_strong. - |
Familial Mediterranean fever, autosomal dominant Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 29, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | May 06, 2022 | ACMG criteria used to clasify this variant: PP1, PS3, PM1, PS4, PM5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 09, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Jul 20, 2024 | ACMG Criteria: PS3, PS4, PM1, PM3, PM5, PP5; Variant was found in heterozygous state - |
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Feb 05, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 10, 2023 | ACMG classification criteria: PS3 supporting, PM3 very strong, PM5 moderated, PP1 strong - |
Familial Mediterranean fever;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2020 | - - |
| 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.Met694Val (c.2080A>G): This variant is one of the most common pathogenic variants for Familial Mediterranean Fever (FMF). This variant has been reported in several publications in individuals with FMF in the homozygous, heterozygous and compound heterozygous state, including a Genereviews entry describing this variant as disease causing (Selected Publications: International FMF Consortium 1997 PMID:8288758, Barut 2018 PMID:28828621, Kriegshauser 2018 PMID:29543225). This variant is present in 0.01% (12/68010) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3243407-T-C?dataset=gnomad_r3). 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:2538). In summary, this variant is classified as pathogenic based on the data above. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
MEFV-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 05, 2024 | The MEFV c.2080A>G variant is predicted to result in the amino acid substitution p.Met694Val. This variant is one of the most common pathogenic variants identified in patients with familial Mediterranean fever (FMF; Moradian et al. 2013. PubMed ID: 23907647; Comak et al. 2013. PubMed ID: 23588594; Sedivá et al. 2014. PubMed ID: 24251727). This variant has been identified in patients in the homozygous and compound heterozygous states, as well as in heterozygous carriers with clinical manifestations of FMF (Moradian et al. 2013. PubMed ID: 23907647; Sedivá et al. 2014. PubMed ID: 24251727). This variant is reported in 0.046% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant is a common cause of familial Mediterranean fever (FMF), and has been previously reported as a heterozygous, compound heterozygous, and homozygous change in patients with MEFV-related disorders (PMID: 9288758, 20301405). Functional studies have shown that this missense change has a damaging effect on the function of the MEFV protein (PMID: 24318677). It is present in the gnomAD population database at a frequency of 0.027% (77/282876) and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.2080A>G (p.Met694Val) variant is classified as Pathogenic. - |
Cryptorchidism;C0036572:Seizure;C0557874:Global developmental delay;C0948163:Abnormal cerebral white matter morphology;C1842364:Central hypotonia;C1857953:Deep plantar creases;C2243051:Macrocephaly;C4025875:Abnormal anterior fontanelle morphology Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | - | - - |
Acute febrile neutrophilic dermatosis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 25, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PS4_Supp,PM1,PM3. - |
Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 06, 2018 | The p.M694V pathogenic mutation (also known as c.2080A>G), located in coding exon 10 of the MEFV gene, results from an A to G substitution at nucleotide position 2080. The methionine at codon 694 is replaced by valine, an amino acid with highly similar properties. This is one of the most common mutations in individuals with familial Mediterranean fever (FMF), particularly among individuals of North African Jewish descent. In addition, homozygosity of the p.M694V mutation is associated with a severe phenotype and 6-fold higher risk of amyloidosis compared with other genotypes (The International FMF Consortium. Cell, 1997 Aug;90:797-807; Gershoni-Baruch R et al. Eur. J. Hum. Genet., 2002 Feb;10:145-9; Kasifoglu T et al. Rheumatology (Oxford), 2014 Apr;53:741-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Stereotypic movement disorder;C0221357:Brachydactyly;C0424503:Abnormal facial shape;C0431447:Synophrys;C0856975:Autistic behavior;C1858120:Generalized hypotonia;C3553450:Profound global developmental delay;C4021798:Abnormal nonverbal communicative behavior;C4551563:Microcephaly Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | - | - - |
Autoinflammatory syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 19, 2022 | - - |
Recurrent fever Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Sep 06, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.
MutationTaster
Benign
D;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
P;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at