ClinVar

Description

Variant summary: CLN8 c.709G>A (p.Gly237Arg) results in a non-conservative amino acid change located in the TRAM/LAG1/CLN8 homology domain (IPR006634) 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 2e-05 in 251492 control chromosomes (gnomAD). c.709G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis, CLN8-Related (Northern Epilepsy) (example, Siintola_2006, Kousi_2009, Kousi_2011, Reinhardt_2010 and Yldirm_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, ultrastructural analysis of lymphocytes from a homozygous patient have demonstrated curvilinear profiles and granular osmiophilic deposit like patterns of lysosomal storage material (example, Reinhardt_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.