ClinVar Genomic variation as it relates to human health

The p.I591T variant (also known as c.1772T>C), located in coding exon 9 of the MEFV gene, results from a T to C substitution at nucleotide position 1772. The isoleucine at codon 591 is replaced by threonine, an amino acid with similar properties. This variant was reported in Spanish kindred in which the proband, a 25 year old male, exhibited recurrent fever accompanied by abdominal pain and synovitis; renal function was normal, no amyloid deposition was observed, and he was responsive to colchicine treatment. The p.I591T alteration was confirmed to be in trans (on the opposite chromosomes) with the p.M694I mutation; each of the his asymptomatic parents carried one alteration. In addition, his two siblings, ages 34 and 35, were also compound heterozygous for p.I591T and p.M694I but were asymptomatic (Aldea A et al. Hum Mutat. 2002;20:148-150). In a study of 71 unrelated patients with a clinical diagnosis of familial Mediterranean fever (FMF), one patient was found to carry both p.I591T alteration and the p.M694I mutation, however the phase (cis vs. trans) was not described (Ait-Idir D et al. Rheumatology (Oxford), 2011 Dec;50:2306-10). In a recent study of clinical and genetic features of adults with autoinflammatory disease, one patient with FMF was heterozygous for this alteration and a benign polymorphism in MEFV; a second patient, with a primary diagnosis of tumor necrosis factor-receptor associated periodic syndrome (TRAPS) was also heterozygous for p.I591T, was reported to have clinical overlap with FMF, and was responsive to colchicine treatment (Hernández-Rodríguez J et al. Autoimmun Rev, 2016 Jan;15:9-15). This variant was previously reported in the SNPDatabase as rs11466045. Based on data from the 1000 Genomes Project, the C allele has an overall frequency of approximately 0.76% (16/2098) total alleles studied. The highest observed frequency was 3.57% (1/28) Spanish alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 1.08% (140/12994) total alleles studied, having been observed in 0.2% (9/4394) African American alleles and 1.52% (131/8600) European American alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4.

Across a selection of available literature, the MEFV c.1772T>C (p.Ile591Thr) missense variant has been identified in a total of 17 patients with familial Mediterranean fever (FMF), including in a compound heterozygous state in five patients and in a heterozygous state in twelve patients (Touitou 2001; Aldea et al. 2002; Tchernitchko et al. 2005; Fisher et al. 2005; Cañete et al. 2007; Ustek et al. 2008; Cornelius et al. 2011; Ait-Idir et al. 2011; Ceylan et al. 2012; Hernández-Rodríguez et al. 2016). Additionally, Aldea et al. (2002) reported the p.Ile591Thr variant in one affected individual in a compound heterozygous state with another known pathogenic variant. However, two siblings who also carried both of the identified variants were asymptomatic, suggesting that the p.Ile591Thr variant may not be disease-causing. This variant was found in six of 1310 control chromosomes (Aldea et al. 2002; Cañete et al. 2007; Ustek et al. 2008; Ait-Idir et al. 2011) and is reported at a frequency of 0.02336 in the Toscani in Italia population of the 1000 Genomes Project. Additionally, twenty three homozygotes are present in the Genome Aggregation Database. Based on the combined evidence, this variant does not appear to be disease-causing in the same manner as known pathogenic FMF variants, but some of the studies suggest that this variant may be a risk allele, modifier or mild allele that displays low penetrance. The p.Ile591Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for familial Mediterranean fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30476289, 29239128, 28748511, 29735907, 28191008, 29047407, 28386255, 28236224, 27943240, 28624931, 28302131, 28631068, 29178647, 28194777, 28158814, 27535533, 21228398, 16255051, 11464238, 17665427, 26299986, 20041150, 22995991, 16100353, 20721559, 12124996)

Variant summary: MEFV c.1772T>C (p.Ile591Thr) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. A recent report utilizing the meta predictor tool, REVEL (Rare Exome Variant Ensemble Learner) to assess the pathogenicity of MEFV variants with ambiguous classification proposed a likely benign outcome for this variant (Accetturo_2019). In this study, REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Auto Inflammatory Diseases. The variant allele was found at a frequency of 0.011 in 285086 control chromosomes, including 24 homozygotes (gnomAD and publication data). It was predominantly found within the European Finnish and non-Finnish subpopulations at a frequency of 0.021 and 0.017, respectively. These frequencies are close to the maximum expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.022). Additionally, the variant was reported with even higher frequencies in the 1000 Genomes Project within the British (0.022) and Toscani (Italian) (0.0234) subpopulation, suggesting this variant is likely a benign polymorphism found primarily in the populations of European origin. This variant has been mostly reported in heterozygous state in patients with Familial Mediterranean Fever (FMF), together with limited reports of compound heterozygosity in multiple ethnicities, without strong evidence for causality (e.g. Fisher 2005, Ait-Idir 2011, Lainka 2012, Papa 2017, Gumus 2018, Stella 2019). Additionally, in a Spanish family, the variant did not co-segregate with the disease, suggestive of an incomplete penetrance or a mostly benign impact (Aldea 2002). In a recent study the variant was found in heterozygous state in a cohort of FMF patients with a similar allele frequency (0.0113), as it was reported in controls in the gnomAD database (Balta_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and the Gene Reviews database have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=1), VUS (n=4), likely benign (n=3) / benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

MEFV NM_000243.2 exon9 p.Ile591Thr (c.1772T>C): This variant has been reported in the literature as a compound heterozygote in at least 2 individuals with Familial Mediterranean Fever (FMF) as well as a heterozygote in at least 5 individuals with FMF (Aldea 2002 PMID:12124996, Tchernitchko 2005 PMID:16255051, Ustek 2008 PMID:19026119, Toutou 2010 PMID:11464238, Ait-Idir 2011 PMID:22019805, Ceylan 2012 PMID:22614345). This variant is present in 2.1% (526/25104) of Finnish alleles, including 2 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/16-3293880-A-G). This variant is present in ClinVar (Variation ID:36506). This variant amino acid Threonine (Thr) is present in >10 species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, despite the high minor allele frequency, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

MEFV: PM5, BP4, BS1, BS2