ClinVar Genomic variation as it relates to human health

Variant summary: CLN8 c.71G>A (p.Arg24His) 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 2e-05 in 251482 control chromosomes (gnomAD). c.71G>A has been reported in the literature as a heterozygous genotype in individuals affected with autism spectrum disorder, without strong evidence for causality (e.g. Egawa_2015). This report does not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no occurrences of the variant in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) or other CLN8-related disorders and no experimental evidence demonstrating an impact on protein function have been reported. Another variant affecting the same codon, c.70C>G (p.Arg24Gly), has been reported in Finnish individuals affected with Northern Epilepsy (HGMD database) and has been classified as pathogenic in ClinVar, suggesting Arg24 may be important for normal protein function. The following publication has been ascertained in the context of this evaluation (PMID: 25806950). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This variant has not been reported in the literature in individuals affected with CLN8-related conditions. This variant is present in population databases (rs762079123, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 24 of the CLN8 protein (p.Arg24His). ClinVar contains an entry for this variant (Variation ID: 2056379). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg24 amino acid residue in CLN8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10508524, 16828266). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLN8 protein function.