ClinVar Genomic variation as it relates to human health

Variant summary: MEFV c.1318C>G (p.Gln440Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251484 control chromosomes, predominantly at a frequency of 0.013 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. This frequency is close to that estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.013 vs 0.022), suggestive of a benign outcome. c.1318C>G has been reported in the literature as a likely benign variant using Rare Exome Variant Ensemble Learner (REVEL), a recently developed variant metapredictor tool. This proposed classification has also been validated by the INFEVERS database (example, Accetturo_2020). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.

The MEFV c.1318C>G; p.Gln440Glu variant (rs11466026) has been described in an individual with periodic fever adenitis pharyngitis aphthous ulcer syndrome (see link below), but has been described as likely benign due to allele frequency and prediction of functional impact (Accetturo 2020, Moradian 2017). The variant is reported in the ClinVar database (Variation ID: 36499) and is reported in the African population with an allele frequency of 1.2% (297/24962 alleles including 1 homozygote) in the Genome Aggregation Database. The glutamine at codon 440 is moderately conserved, but computational analyses predict that this variant is neutral (REVEL: 0.124). Although this variant has been described with a relatively high population frequency, we cannot exclude the possibility that this is a mild pathogenic variant. However, given the lack of clinical and functional data, the significance of the p.Gln440Glu variant is uncertain at this time. References: Link to MEFV Q440E in Infevers database: https://infevers.umai-montpellier.fr/web/search.php?n=1 Accetturo M et al. Improvement of MEFV gene variants classification to aid treatment decision making in familial Mediterranean fever. Rheumatology (Oxford). 2020 Apr 1;59(4):754-761. PMID: 31411330. 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. PMID: 29178647.

Reported in InFevers database in a patient with periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) syndrome (Cazeneuve et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 29178647, 28421071, 25760918, 24117178)

MEFV NM_000243.2 exon 4 p.Gln440Glu (c.1318C>G): This variant has not been reported in the literature but has been identified in 1 individual with PFAPA (periodic fevers with apthous stomatits, pharyngitis and adenitis) syndrome in the Infevers database (https://infevers.umai-montpellier.fr/). This variant is present in 1% (297/24962) of African alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3298947-G-C). This variant is present in ClinVar (Variation ID:36499). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

ACMG classification criteria: BP4, BP6

MEFV NM_000243.2 exon 4 p.Gln440Glu (c.1318C>G): This variant has not been reported in the literature but has been identified in 1 individual with PFAPA (periodic fevers with apthous stomatits, pharyngitis and adenitis) syndrome in the Infevers database (https://infevers.umai-montpellier.fr/). This variant is present in 1% (297/24962) of African alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3298947-G-C). This variant is present in ClinVar (Variation ID:36499). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.