rs104895076
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_000243.3(MEFV):c.443A>T(p.Glu148Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000393 in 1,604,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E148Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000243.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000768 AC: 18AN: 234246Hom.: 0 AF XY: 0.000100 AC XY: 13AN XY: 129380
GnomAD4 exome AF: 0.0000413 AC: 60AN: 1452652Hom.: 0 Cov.: 61 AF XY: 0.0000512 AC XY: 37AN XY: 722468
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152278Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74466
ClinVar
Submissions by phenotype
Familial Mediterranean fever Pathogenic:1Uncertain:3Benign:1Other:1
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2002 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2025 | This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 148 of the MEFV protein (p.Glu148Val). This variant is present in population databases (rs104895076, gnomAD 0.04%). This missense change has been observed in individual(s) with familial mediterranean fever (PMID: 17489852, 24469716, 28211254, 28483595, 29735907). ClinVar contains an entry for this variant (Variation ID: 2554). 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 disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Dec 19, 2024 | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2025 | MEFV: PM2:Supporting, BP4 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25449140, 31411330, 23289470, 23588594, 28597968, 28483595, 29735907, 26585190, 30783801, 30874249, 30915208, 29756710, 28211254, 27170062, 34426522, 26247045, 35358658, 33576586, 26003477, 32199921, 22451026) - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 28, 2025 | Variant summary: MEFV c.443A>T (p.Glu148Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. A recently reported in-silico ensemble method for predicting pathogenicity of missense variants (Rare Exome Variant Ensemble Learner, REVEL) predicted a computed classification for this variant as likely pathogenic (Accetturo_2020). The variant allele was found at a frequency of 7.7e-05 in 235044 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (7.7e-05 vs 0.022), allowing no conclusion about variant significance. Following a comprehensive and conservative assessment of literature spanning over thirteen years (2007-2020), c.443A>T, has been reported in the literature in a homozygous/compound heterozygous genotype in multiple individuals affected with Familial Mediterranean Fever (example, Giaglis_2007, Ibrahim_2015, Lachmann_2006, Cekin_2017, Sandhya_2017, Gumus_2018, Bozgeyik_2020, Tanatar_2020). Numerous publications also reported affected individuals lacking a second allele. In addition, the variant has also been reported in asymptomatic individuals. At-least one co-occurrence in cis with another pathogenic MEFV variant (p.M694V Tchernitchko 2003) has been ascertained in the context of this evaluation. Variable reports of the extent of genotyping and lack of clearly defined phase information (i.e., presumed trans versus cis co-occurrence) confound an accurate assessment from the ascertained literature. These data indicate that the variant may be associated with disease in some genetic backgrounds. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31411330, 21413889, 32199921, 28483595, 26028444, 23588594, 26003477, 22451026, 17489852, 29735907, 26585190, 15475974, 28597968, 16403826, 22903357, 11903360, 14578333, 23463692, 24469716, 29047407, 28211254, 31646357, 14578331, 15502081, 15643295). ClinVar contains an entry for this variant (Variation ID: 2554). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 30, 2018 | The MEFV c.443A>T; p.Glu148Val variant (rs104895076), is reported in the literature in the heterozygous, compound heterozygous, and homozygous state in individuals with a variety of symptoms, ranging from no symptoms to juvenile idiopathic arthritis to familial Mediterranean fever (Comak 2013, Dogan 2013, Dogan 2015, Giaglis 2007, Medlej-Hashim 2002, Sandhya 2017). This variant is reported in ClinVar (Variation ID: 2554), and is found in the South Asian population with an allele frequency of 0.043% (13/30,272 alleles) in the Genome Aggregation Database. The glutamic acid at codon 148 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to conflicting phenotype information, the clinical significance of the p.Glu148Val variant is uncertain at this time. References: Comak E et al. MEFV gene mutations in Turkish children with juvenile idiopathic arthritis. Eur J Pediatr. 2013 Aug;172(8):1061-7. Dogan CS et al. Prevalence and significance of the MEFV gene mutations in childhood Henoch-Schonlein purpura without FMF symptoms. Rheumatol Int. 2013 Feb;33(2):377-80. Dogan H et al. Familial Mediterranean fever gene mutations in north-eastern part of Anatolia with special respect to rare mutations. Gene. 2015 Sep 1;568(2):170-5. Giaglis S et al. MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever. Clin Genet. 2007 May;71(5):458-67. Medlej-Hashim M et al. Familial Mediterranean fever: the potential for misdiagnosis of E148V using the E148Q usual RFLP detection method. Clin Genet. 2002 Jan;61(1):71-3. Sandhya P et al. Egyptian tale from India: application of whole-exome sequencing in diagnosis of atypical familial Mediterranean fever. Int J Rheum Dis. 2017 Nov;20(11):1770-1775. - |
Familial Mediterranean fever, autosomal dominant Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 30, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Familial Mediterranean fever;C0085077:Acute febrile neutrophilic dermatosis;C1851347:Familial Mediterranean fever, autosomal dominant Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 09, 2024 | - - |
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2017 | - - |
Acute febrile neutrophilic dermatosis Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at