ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1318C>G (p.Gln440Glu) (rs11466026)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586627 SCV000279048 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing The Q440E variant has been reported previously in a patient with periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) syndrome and in a heterozygous carrier with limited evidence for pathogenicity (Cazeneuve et al., 2007; Berg et al., 2013). It is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, per the 1000 Genomes Consortium, the Q440E variant was observed at a frequency of 2.57%, 34/1322 alleles, in individuals of African ancestry, including 6.19%, 14/226 alleles, in individuals of Gambian ancestry. In addition, this substitution occurs at a position that is not conserved and in-silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000586627 SCV000604179 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing The MEFV c.1318C>G;p.Gln440Glu variant has been described in an individual with periodic fever adentitis pharyngitis aphthous ulcer syndrome (PFAPA, see link below). The variant is listed in the dbSNP variant database (rs11466026) with an allele frequency of up to 1.0924 percent (48/4346 alleles) in the African American population in the Exome Variant Server , 1.211 percent in the African population in the Genome Aggregation Database (291/24026 alleles, 1 homozygote), and up to 6.2 percent (14/212 alleles) in a specific African subset population in the 1000 Genomes Project (2.6 percent (34/1288 alleles) in the general African population). The variant is listed in the ClinVar database (Variation ID: 36499). The amino acid at this position is moderately conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is tolerated. Although this variant has been described with a relatively high population frequency, we cannot exclude the possibility that this is a mild pathogenic variant. Therefore, the clinical significance of this variant is uncertain. References: Link to MEFV Q440E in Infevers database:
Invitae RCV000989483 SCV000629020 benign Familial Mediterranean fever 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586627 SCV000696044 uncertain significance not provided 2016-09-21 criteria provided, single submitter clinical testing Variant summary: The MEFV c.1318C>G (p.Gln440Glu) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 179/121412 control chromosomes at a frequency of 0.0014743, which does not exceed the estimated maximal expected allele frequency of a pathogenic MEFV variant (0.0216506). The variant has been reported in the infevers database in a patient with PFAPA Syndrome, without strong evidence for causality. One clinical diagnostic laboratory/reputable database has classified this variant as a VUS. Taken together, this variant is classified as VUS until additional evidence becomes available.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000586627 SCV000701934 uncertain significance not provided 2016-10-03 criteria provided, single submitter clinical testing
Mendelics RCV000989483 SCV001139860 uncertain significance Familial Mediterranean fever 2019-05-28 criteria provided, single submitter clinical testing

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