ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect on enzyme activity (Kaiser FJ, 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32564284, 27535533, 26671848, 22885700, 30293248, 27159028, 24403048)

This missense change has been observed in individual(s) with Cornelia de Lange syndrome or intellectual disability (PMID: 22885700, 24403048, 26671848, 27159028). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HDAC8 function (PMID: 22885700, 24403048, 26725122). 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 not expected to disrupt HDAC8 protein function. ClinVar contains an entry for this variant (Variation ID: 39713). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 320 of the HDAC8 protein (p.Gly320Arg).

The p.G320R variant (also known as c.958G>A), located in coding exon 9 of the HDAC8 gene, results from a G to A substitution at nucleotide position 958. The glycine at codon 320 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified to occur de novo in two males with clinical features consistent with a diagnosis of Cornelia de Lange syndrome (CdLS); however, paternity was not confirmed (Deardorff MA et al. Nature, 2012 Sep;489:313-7; Parenti I et al. Clin. Genet., 2016 May;89:564-73). Functional studies in lymphoblastoid cell lines (LCLs) from a hemizygous male with the p.G320R variant demonstrated that this alteration results in minimal protein expression and decreased deacetylase activity (Deardorff MA et al. Nature, 2012 Sep;489:313-7; Kaiser FJ et al. Hum. Mol. Genet., 2014 Jun;23:2888-900). This alteration was also reported as de novo in a female with synophrys, micrognathia, growth delay, postnatal low weight and height, hypotonia, seizures, moderate intellectual disability with language delay, and autistic traits. Extreme X-chromosome inactivation was observed with only the wild-type allele being expressed in blood, however this may not be representative of other tissues, such as the brain (Fieremans N et al. Hum. Mutat., 2016 Aug;37:804-11). This amino acid position is highly conserved in mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

PS4, PS3, PM1, PM2, PP3, PP5 - This missense variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 39713).In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. It is not present in population databases (gnomAD no frequency). It is reported previously as causative (PMID: 24403048, 26671848). Functional studies support pathogenic effect (PMID: 22885700, 24403048).