Submissions for variant NM_000243.3(MEFV):c.1760-4G>A

gnomAD frequency: 0.00459  dbSNP: rs79662406

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000083710	SCV000629028	benign	Familial Mediterranean fever	2025-01-28	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 Laboratory Services, 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	RCV001572991	SCV001471540	likely benign	not provided	2021-09-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262635	SCV002543721	likely benign	Autoinflammatory syndrome	2021-05-18	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