ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

MEFV NM_000243.2 exon 3 p.Arg329His (c.986G>A): This variant has been reported in the literature in at least 8 individuals with features of Familial Mediterranean Fever (FMF) as heterozygous, at least 1 of whom were identified to have a pathogenic variant in MEFV in trans (p.Met694Ile) (Berdelli 2012 PMID:n/a, Kumpfel 2012 PMID:22337722, Lainka 2012 PMID:22903357, Pauwels 2013 PMID:23325590, Yao 2016 PMID:26620106). In addition, this variant was identified in at least 1 individual with fibromyalgia (Feng 2009 PMID:20041150). This variant is present in 0.2% (63/30562) of South Asian alleles amd 1.1% (111/10,054) of Ashkenazi Jewish alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3299705-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:97557). This variant amino acid Histidine (His) is present in >30 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is conflicting and insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

The MEFV c.986G>A; p.Arg329His variant (rs104895112) has been described in the literature in several individuals affected with familial Mediterranean fever (FMF), atypical FMF, or fibromyalgia (Lainka 2012, Feng 2009, Portincasa 2013, Yao 2016). This variant is listed in ClinVar (Variation ID: 97557) and is found in the general population with an overall allele frequency of 0.16% (441/279644 alleles, including 2 homozygotes) in the Genome Aggregation Database. The arginine at position 329 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.166). Due to the wide range of phenyotypes and lack of functional data, the significance of the p.Arg329His variant is uncertain at this time. References: Lainka E et al. Familial Mediterranean fever in Germany: epidemiological, clinical, and genetic characteristics of a pediatric population. Eur J Pediatr. 2012 Dec;171(12):1775-85. PMID: 22903357. Feng J et al. Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels. PLoS One. 2009. 4(12):e8480. PMID: 20041150. Portincasa P et al. Familial mediterranean fever: a fascinating model of inherited autoinflammatory disorder. Eur J Clin Invest. 2013 Dec;43(12):1314-27. PMID: 24117178. Yao Q et al. Adult autoinflammatory disease frequency and our diagnostic experience in an adult autoinflammatory clinic. Semin Arthritis Rheum. 2016 Apr;45(5):633-7. PMID: 26620106.

MEFV NM_000243.2 exon 3 p.Arg329His (c.986G>A): This variant has been reported in the literature in at least 8 individuals with features of Familial Mediterranean Fever (FMF) as heterozygous, at least 1 of whom were identified to have a pathogenic variant in MEFV in trans (p.Met694Ile) (Berdelli 2012 PMID:n/a, Kumpfel 2012 PMID:22337722, Lainka 2012 PMID:22903357, Pauwels 2013 PMID:23325590, Yao 2016 PMID:26620106). In addition, this variant was identified in at least 1 individual with fibromyalgia (Feng 2009 PMID:20041150). This variant is present in 0.2% (63/30562) of South Asian alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3299705-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:97557). This variant amino acid Histidine (His) is present in >30 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is conflicting and insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Reported in the heterozygous state in multiple unrelated individuals with familial Mediterranean fever (Feng et al., 2009; Lainka et al., 2012; Yao et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26554556, 26247045, 22903357, 29260407, 26620106, 23010357, 23325590, 24117178, 20041150, 29178647, 27838405, 29408806, 23867542, 23070486, 22337722, 31989427, 32271453, 30755392, 35156637)

Variant summary: MEFV c.986G>A (p.Arg329His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 249988 control chromosomes, predominantly at a frequency of 0.0021 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not higher than predicted for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.0016 vs 0.022), allowing no conclusion about variant significance. c.986G>A, has been reported in the literature in patients in association with FMF, atypical FMF, MS and fibromyalgia (e.g. Feng_2009, Kuempfel_2012, Berdeli_2012, Pauwels_2013, Heshin-Bekenstein_2015, Yao_2016, Balta_2018, Zhang_2018). The phenotypic variability seen with this variant and genotypic information are not clearly specific to FMF, and at least some of these reported FMF patients were not responsive to colchicine therapy (Hashkes_2012). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Familial Mediterranean Fever. Recently, the International Study Group for Systemic Autoinflammatory Diseases (INSIAD) involving experts on hereditary recurrent fever genetics, provided a classification of likely benign with a validated status for c.986G>A (Van Gijn_2018). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) and VUS (n=8). At-least one submitter has re-classified this variant as likely benign. Another submitter has cited overlapping evidence utilized in the context of our evaluation. We have followed this variant for over four years and previously classified it as a VUS. In our review of published evidence spanning over 10 years (2009-2019), the majority of evidence appears to point toward a non-pathogenic outcome however more data is required to conclusively determine the clinical consequences of this variant. Therefore, based on the evidence outlined above, this variant in isolation is re-classified as likely benign.

MEFV: BP4, BS1

Variant interpretted as Uncertain significance and reported on 06-02-2016 by Lab or GTR ID 506013. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Variant interpreted as Uncertain significance and reported on 09-17-2019 by LabCorp. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.