ClinVar Genomic variation as it relates to human health

HDAC c.356C>G results in a non-conservative amino acid change (p.Thr119Arg) located in the Histone deacetylase domain of the encoded protein sequence. The variant is classified as pathogenic, since it is absent in population databases, it is predicted as having a deleterious effect by multiple computational analyses and it is a de novo variant. Moreover, a c.356C>T transition has been described (Yuan et al., 2015) and two clinical diagnostic laboratories submitted pathogenic classifications for this variant to ClinVar. To date, 48 unique deleterious variants have been reported in HDAC8 and associated to Cornelia de Lange syndrome 5. By molecular modeling, the amino acid change compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function, triggering global structural changes that propagate through the protein scaffold to the catalytic site, creating de facto haploinsufficiency. The effects observed are similar of those described by Decroos and colleagues regarding the p.Gly117Glu replacement, which compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function, resulting in a 5% residual enzyme activity.

A heterozygous missense variation in exon 4 of the HDAC8 gene that results in the amino acid substitution of Arginine for Threonine at codon 119 was detected. The observed variant c.356C>G(p.Thr119Arg) not been reported in the 1000 genomes, ExAC and our internal databases. The in silico prediction of the variant is probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT, damaging by LRT and MutationTaster2. The reference codon is conserved across species. Segregation analysis suggests the variant to be of de novo origin. In summary, the variant meets our criteria to be classified as pathogenic.