ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.124C>T (p.Arg42Trp) (rs61754767)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000757453 SCV000279020 uncertain significance not provided 2017-10-13 criteria provided, single submitter clinical testing The R42W variant in the MEFV gene has been reported in the heterozygous state 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). The NHLBI ESP Exome Sequencing Project reports R42W was observed in 0.43% (19/4394) alleles from individuals of African American ancestry, indicating it may be a rare benign variant in this population with no homozygous individuals reported. Although R42W occurs at a position that is not conserved, it is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, in vitro studies of this variant suggest it results in slightly reduced interaction and may facilitate activation of the pyrin inflammasome, with limited evidence for pathogenicity (Vajjhala et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000632798 SCV000753988 likely benign Familial Mediterranean fever 2017-11-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757453 SCV000885685 uncertain significance not provided 2018-03-07 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% (97/24032 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.
Integrated Genetics/Laboratory Corporation of America RCV000780402 SCV000917624 uncertain significance not specified 2018-10-05 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 277224 control chromosomes, predominantly within the African subpopulation at a frequency of 0.004 in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.0004 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, however without strong evidence for pathogenicity (e.g. Moradian 2017). Therefore these data do not allow any conclusion 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). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one classifying the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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