ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.443A>T (p.Glu148Val) (rs104895076)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000216721 SCV000052849 uncertain significance not specified 2020-12-31 criteria provided, single submitter clinical testing 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 7.2e-05 in 263010 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (7.2e-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. Four ClinVar submissions from clinical diagnostic laboratories (evaluations after 2014) cite the variant as "uncertain significance." Some submitters cite overlapping evidence utilized in the context of this evaluation. Therefore, due to the conflicting evidence outlined above, the variant has been classified as VUS-possibly pathogenic.
GeneDx RCV000216721 SCV000279032 uncertain significance not specified 2015-09-29 criteria provided, single submitter clinical testing The E148V variant of unknown significance has been previously published in association with familial Mediterranean fever and juvenile idopathic arthritis (Sever et al., 2012; Comak et al., 2013). It was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E148V is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to glutamic acid are tolerated across species. However, in-silico analysis predicts this variant is probably damaging to the protein structure/function. Missense pathogenic variants at the same codon (E148Q) and in nearby residues (S141I, R143P) have also been reported in the Human Gene Pathogenic variant Database in association with familial Mediterranean fever (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415966 SCV000493691 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000216721 SCV001156673 uncertain significance not specified 2018-10-30 criteria provided, single submitter clinical testing 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.
Invitae RCV000002663 SCV001412934 uncertain significance Familial Mediterranean fever 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with valine at codon 148 of the MEFV protein (p.Glu148Val). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is present in population databases (rs104895076, ExAC 0.05%). This variant has been observed in individual(s) with familial mediterranean fever (PMID: 28211254, 17489852, 24469716, 29735907, 28483595). ClinVar contains an entry for this variant (Variation ID: 2554). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
OMIM RCV000002663 SCV000022821 pathogenic Familial Mediterranean fever 2002-01-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000002663 SCV000115872 not provided Familial Mediterranean fever no assertion provided not provided
Natera, Inc. RCV000002663 SCV001452090 uncertain significance Familial Mediterranean fever 2020-09-16 no assertion criteria provided clinical testing

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