ClinVar Genomic variation as it relates to human health

The missense c.688G>A p.Glu230Lys variant in MEFV gene has been reported previously in compound heterozygous state in individuals affected with Familial Mediterranean fever FMF Timmann et al., 2001. This variant is reported with the allele frequency of 0.06% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Glu at position 230 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu230Lys in MEFV is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Uncertain Significance.

MEFV NM_000243.2 exon 2 p.Glu230Lys (c.688G>A): This variant has been reported in the literature in at least 3 individuals with features of Familial Mediteranean Fever (FMF), at least one of whom represented a compound heterozygote in trans with a known pathogenic variant (Timmann 2001 PMID:1147095, Touitou 2001 PMID:11464238, Ceylan 2012 PMID:29178647). In addition, this variant was also identified in 1 individual with features of FMF and multiple sclerosis (Blaschek 2010 PMID:20876156). This variant is present in 0.4% (143/30614) of South Asian alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3304380-C-T). This variant is present in ClinVar (Variation ID:97537). Evolutionary conservation for this variant is unclear; however, this variant Lysine (Lys) is present in 2 primates. 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.

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 2 p.Glu230Lys (c.688G>A): This variant has been reported in the literature in at least 3 individuals with features of Familial Mediteranean Fever (FMF), at least one of whom represented a compound heterozygote in trans with a known pathogenic variant (Timmann 2001 PMID:1147095, Touitou 2001 PMID:11464238, Ceylan 2012 PMID:29178647). In addition, this variant was also identified in 1 individual with features of FMF and multiple sclerosis (Blaschek 2010 PMID:20876156). This variant is present in 0.4% (143/30614) of South Asian alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3304380-C-T). This variant is present in ClinVar (Variation ID:97537). Evolutionary conservation for this variant is unclear; however, this variant Lysine (Lys) is present in 2 primates. 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.

Variant summary: MEFV c.688G>A (p.Glu230Lys) results in a 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 0.00063 in 249694 control chromosomes, predominantly at a frequency of 0.0047 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.00063 vs 0.022), allowing no conclusion about variant significance. c.688G>A has been reported in the literature as homozygous and compound heterozygous genotypes in individuals reportedly meeting the clinical diagnostic criteria for Familial Mediterranean Fever (FMF) (example, Timmann_2001, Kallinich_2010, Berdelli_2011, Lainka_2012, Omenetti_2013, Gohar_2016, Arpaci_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as VUS (n=8) (Likely Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

Observed with a pathogenic variant in additional patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 22903357, 24469716); Observed in apparent homozygous state in a patient with familial Mediterranean fever in the literature, however, also observed in the homozygous state in controls (PMID: 21413889; gnomAD; internal data); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20876156, 22614345, 11464238, 33083013, 24929125, 24233262, 26215181, 24469716, 22903357, 35358658, 17489852, 19762364, 36321013, 31803701, 33738724, 35298548, 28943464, 29178647, 29735907, 28421071, 31989427, 35480407, 28927886, 29393966, 32082075, ebnem-ZEMR-SA[CaseReport]2019, 23505242, 27333294, 11470495, 21413889)

MEFV: PM3:Strong, PM2:Supporting, BP4