Submissions for variant NM_000243.3(MEFV):c.124C>T (p.Arg42Trp)

gnomAD frequency: 0.00121  dbSNP: rs61754767

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000757453	SCV000279020	uncertain significance	not provided	2020-09-02	criteria provided, single submitter	clinical testing	Observed in the heterozygous state with and without other variants in patients with familial Mediterranean fever and was observed at a frequency of 0.5% in a study of Armenian patients with FMF (Touitou et al., 2001; Sarkisian et al., 2005; Moradian et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 14527383, 21228398, 11464238, 19505404, 25006247, 15641782, 14527388, 25451010, 20485448, 15951859, 15720244, 15502081, 12496512, 29178647, 15720238)
Invitae	RCV000632798	SCV000753988	likely benign	Familial Mediterranean fever	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757453	SCV000885685	uncertain significance	not provided	2020-03-03	criteria provided, single submitter	clinical testing	The MEFV c.124C>T; p.Arg42Trp variant (rs61754767) is reported in the medical literature in one individual with familial Mediterranean fever (Touitou 2001). The variant protein is also described as having at least some altered function (Vajjhala 2014), but the variant is also described as not occurring in the same region as known pathogenic variants (Moradian 2017). The variant is reported in the ClinVar database (Variation ID: 234347). This variant is found in the population with an overall allele frequency of 0.4% (97/24,032 alleles) in the Genome Aggregation Database. The arginine at this position is moderately conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, there is insufficient evidence to classify this variant with certainty. REFERENCES Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001 Jul;9(7):473-83. Moradian MM et al. Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF. Mol Genet Genomic Med. 2017 Nov;5(6):742-750. Vajjhala PR et al. Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly. J Biol Chem. 2014 Aug 22;289(34):23504-19.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780402	SCV000917624	uncertain significance	not specified	2022-08-11	criteria provided, single submitter	clinical testing	Variant summary: MEFV c.124C>T (p.Arg42Trp) results in a non-conservative amino acid change located in the DAPIN domain (also called pyrin domain (PYD), IPR004020) which is a protein-protein interaction domain involved in inflammasome assembly (Vajjhala_2014). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 282866 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.004, including 1 homozygote in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.004 vs 0.022), allowing no conclusion about variant significance. c.124C>T has been reported in the literature in individuals affected with Familial Mediterranean Fever (FMF), however without strong evidence for pathogenicity (e.g. Moradian_2017). Therefore these data do not allow clear conclusions about variant significance. At least one publication reports experimental evidence on protein function, demonstrating an increased protein stability, possibly decreased auto-inhibition, but also a decreased protein-protein interaction (with ASC) that is important for the inflammasome assembly; the authors of this study hypothesized that the overall effects of the variant might contribute to FMF by facilitating activation of the pyrin inflammasome (Vajjhala_2014). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, four classifying the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000632798	SCV001139898	uncertain significance	Familial Mediterranean fever	2019-05-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262821	SCV002543696	uncertain significance	Autoinflammatory syndrome	2017-04-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000757453	SCV001928264	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000757453	SCV001971453	uncertain significance	not provided		no assertion criteria provided	clinical testing