Submissions for variant NM_000243.3(MEFV):c.2292G>T (p.Gly764=)

gnomAD frequency: 0.00034  dbSNP: rs142352887

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429125	SCV000513594	uncertain significance	not provided	2021-10-25	criteria provided, single submitter	clinical testing	In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 24158885)
Invitae	RCV000989470	SCV001097721	likely benign	Familial Mediterranean fever	2024-01-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000989470	SCV001139806	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000190	SCV001156687	uncertain significance	not specified	2019-06-05	criteria provided, single submitter	clinical testing	The MEFV c.2292G>T; p.Gly764Gly variant (rs142352887) is reported in the medical literature in an individual with a clinical diagnosis of FMF (Jeske 2013). However, the variant has also been described as likely benign by a group of experts (Van Gijn 2018). The variant is described in the ClinVar database (Variation ID: 378133) and in the general population with an allele frequency of 0.02% (63/282832 alleles) in the Genome Aggregation Database. This is a synonymous variant in a weakly conserved nucleotide but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site, removing a portion of the pyrin domain. Due to conflicting information, the clinical significance of the variant is uncertain at this time. References: Jeske M et al. Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study. Klin Padiatr. 2013 Nov;225(6):325-30. Van Gijn ME et al. New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID). J Med Genet. 2018 Aug;55(8):530-537.
CeGaT Center for Human Genetics Tuebingen	RCV000429125	SCV001501589	likely benign	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263677	SCV002543743	uncertain significance	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001000190	SCV004804028	uncertain significance	not specified	2024-01-31	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.2292G>T alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 251442 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00021 vs 0.022), allowing no conclusion about variant significance. c.2292G>T has been reported in the literature in heterozygous individuals affected with Familial Mediterranean Fever (e.g. Jeske_2013, Hageman_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. 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: 31264586, 24158885, 24117178). ClinVar contains an entry for this variant (Variation ID: 378133). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000989470	SCV001458293	likely benign	Familial Mediterranean fever	2020-01-09	no assertion criteria provided	clinical testing