ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect with reduction of protein expression in patient fibroblasts (Edvardson S et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); 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: 31625567, 27807845, 29769041, 28158450)

The missense variant c.1423G>A(p.Ala475Thr) in TBCD gene has been reported in homozygous state in individuals with early-onset encephalopathy with brain atrophy and thin corpus callosum (Stephen J, et al., 2018). Experimental studes have shown that this missense change alters TBCD gene expression (Pode-Shakked B,et al., 2017). The variant has 0.001% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Alanine at position 475 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by SIFT. The amino acid change p.Ala475Thr in TBCD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 475 of the TBCD protein (p.Ala475Thr). This variant is present in population databases (rs775014444, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of progressive early-onset encephalopathy with brain atrophy and thin corpus callosum (PMID: 27807845, 28158450, 29769041). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279953). 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 TBCD protein function. Studies have shown that this missense change alters TBCD gene expression (PMID: 27807845). For these reasons, this variant has been classified as Pathogenic.

Variant summary: TBCD c.1423G>A (p.Ala475Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248244 control chromosomes (gnomAD). c.1423G>A has been reported in the literature in multiple individuals affected with infantile neurodegenerative disorders including Encephalopathy, Early Onset (e.g. Edvardson_2016, AlAbdi_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding ~10% of normal TBCD intracellular abundance in fibroblasts from homozygous patient fibroblasts (Edvardson_2016). The following publications have been ascertained in the context of this evaluation (PMID: 28158450, 37644014). ClinVar contains an entry for this variant (Variation ID: 279953). Based on the evidence outlined above, the variant was classified as pathogenic.