ClinVar Miner

Submissions for variant NM_000243.3(MEFV):c.2078TGA[1] (p.Met694del) (rs104895091)

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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 RCV000083740 SCV000696057 pathogenic Familial Mediterranean fever 2016-06-13 criteria provided, single submitter clinical testing Variant summary: The MEFV c.2081_2083delTGA (p.Met694del) variant involves an in-frame deletion of three nucleotides. One in silico tool predicts a benign outcome for this variant. The variant is absent in 121410 control chromosomes while it was reported in several FMF patients in heterozygosity indicating a dominant inheritance. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757455 SCV000885687 pathogenic not provided 2018-05-09 criteria provided, single submitter clinical testing The MEFV c.2081_2083delTGA; p.Met694del variant (rs104895091) is described in the medical literature in several individuals and families with a clinical diagnosis of familial Mediterranean fever often in individuals without an additional pathogenic variant (Booth 2000, Rowczenio 2017), but also in two individuals with an additional pathogenic variant (Belmahi 2012). The variant is listed as pathogenic by several sources in the ClinVar database (Variation ID: 2556) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at this position is moderately conserved across species and other variants in this codon are considered pathogenic (Variation IDs: 2539, 2538). Considering available information, this variant is classified as pathogenic. References: Belmahi L et al. MEFV mutations in Moroccan patients suffering from familial Mediterranean Fever. Rheumatol Int. 2012 Apr;32(4):981-4. Booth DR et al. The genetic basis of autosomal dominant familial Mediterranean fever. QJM. 2000 Apr;93(4):217-21. Rowczenio DM et al. Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue-a case series and genetic exploration. Rheumatology (Oxford). 2017 Feb;56(2):209-213.
Mendelics RCV000083740 SCV001139822 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000083740 SCV001491922 uncertain significance Familial Mediterranean fever 2020-07-15 criteria provided, single submitter clinical testing This variant, c.2081_2083del, results in the deletion of 1 amino acid(s) of the MEFV protein (p.Met694del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial Mediterranean fever (PMID: 10024914, 10787449, 29047407, 19479870, 21246368). ClinVar contains an entry for this variant (Variation ID: 2556). 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: 23334425, 10787449, 12064853). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 RCV000002665 SCV000022823 pathogenic Familial mediterranean fever, autosomal dominant 2000-04-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083740 SCV000115833 not provided Familial Mediterranean fever no assertion provided not provided
GeneReviews RCV000083740 SCV000484969 pathogenic Familial Mediterranean fever 2016-12-15 no assertion criteria provided literature only
Natera, Inc. RCV000083740 SCV001462096 pathogenic Familial Mediterranean fever 2020-09-16 no assertion criteria provided clinical testing

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