ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1760-4G>A (rs79662406)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000246189 SCV000303121 benign not specified criteria provided, single submitter clinical testing
GeneDx RCV001572991 SCV000513593 benign not provided 2019-02-04 criteria provided, single submitter clinical testing
Invitae RCV000083710 SCV000629028 benign Familial Mediterranean fever 2020-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000246189 SCV000917631 benign not specified 2021-01-14 criteria provided, single submitter clinical testing Variant summary: MEFV c.1760-4G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 250940 control chromosomes, predominantly at a frequency of 0.017 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. This frequency is not significantly higher (somewhat lower) than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.0012 vs 0.022), allowing no conclusion about variant significance, however, considering also the several homozygotes, the variant might still represent a benign polymorphism. To our knowledge, no occurrence of c.1760-4G>A in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. The variant, c.1760-4G>A, has been reported by the International Study Group for Systemic Autoinflammatory Diseases (INSAID), with an experts consensus as "likely benign" (Van Gijn_2018). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and predominantly as benign/likely benign (n=3). Based on the evidence outlined above, due to the absence of any actionable evidence supporting an association with disease, the variant was classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000083710 SCV001279832 uncertain significance Familial Mediterranean fever 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285148 SCV001471540 likely benign none provided 2020-03-03 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083710 SCV000115802 not provided Familial Mediterranean fever no assertion provided not provided
Natera, Inc. RCV000083710 SCV001458297 likely benign Familial Mediterranean fever 2020-05-13 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001572991 SCV001798215 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001572991 SCV001929544 likely benign not provided no assertion criteria provided clinical testing

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