ClinVar Genomic variation as it relates to human health

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000381580). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:23881342, 27101822, 29016355, 29774539). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

A Heterozygous Missense variant c.841G>A in Exon 7 of the FBP1 gene that results in the amino acid substitution p.Glu281Lys was identified. The observed variant has a minor allele frequency of 0.00008% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/ Likely Pathogenic with 2 stars, criteria provided, multiple submitters, no conflicts (Variant ID: 381580). This variant has previously been reported for fructose-1,6-bisphosphatase deficiency by Santer R,et,al.,2016. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27101822, 29774539, 29016355, 31584309, 23881342, 33083013, 26549536)

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 281 of the FBP1 protein (p.Glu281Lys). This variant is present in population databases (rs566453434, gnomAD 0.06%). This missense change has been observed in individuals with fructose-1,6-bisphosphatase deficiency (PMID: 23881342, 27101822, 29016355, 29774539; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBP1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Variant summary: FBP1 c.841G>A (p.Glu281Lys) results in a conservative amino acid change located in the fructose-1-6-bisphosphatase class 1, C-terminal domain (IPR044015) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251476 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FBP1 causing Fructose-biphosphatase deficiency, allowing no conclusion about variant significance. c.841G>A has been reported in the literature in the compound heterozygous and homozygous states in multiple individuals affected with Fructose-biphosphatase deficiency (e.g. Afroze_2013, Kato_2015, Bhai_2018). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study in HepG2 cells reports experimental evidence that this variant results in significantly reduced enzyme activity compared to wildtype. The following publications have been ascertained in the context of this evaluation (PMID: 23881342, 29774539, 26549536, 37507476). ClinVar contains an entry for this variant (Variation ID: 381580). Based on the evidence outlined above, the variant was classified as pathogenic.