Submissions for variant NM_018941.4(CLN8):c.470A>G (p.His157Arg)

gnomAD frequency: 0.00003  dbSNP: rs149308952

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192707	SCV000247046	likely pathogenic	Neuronal ceroid lipofuscinosis 8	2015-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307439	SCV002600511	likely pathogenic	Neuronal ceroid lipofuscinosis	2022-10-14	criteria provided, single submitter	clinical testing	Variant summary: CLN8 c.470A>G (p.His157Arg) results in a non-conservative amino acid change located in the TRAM/LAG1/CLN8 homology domain (IPR006634) of 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 1.6e-05 in 251458 control chromosomes (gnomAD). c.470A>G has been reported in the literature in one heterozygous individual affected with Cerebellar Atrophy (Sun_2019), and in one homozygous individual affected with Neuronal Ceroid-Lipofuscinosis (e.g. Kousi_2009, Reinhardt_2010). These data indicate that the variant may be associated with disease. Functional evaluation of the variant protein showed that there was signficantly reduced interaction with lysosomal proteins, with the most pronounced variant effect resulting in <10% of normal activity (di Ronza_2018). Two ClinVar submitters have assessed the variant since 2014 without evidence for independent evaluation: one classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV002307439	SCV003516673	uncertain significance	Neuronal ceroid lipofuscinosis	2022-03-09	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 157 of the CLN8 protein (p.His157Arg). This variant is present in population databases (rs149308952, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of CLN8-related conditions (PMID: 19807737, 29915382). ClinVar contains an entry for this variant (Variation ID: 210736). 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 CLN8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000192707	SCV001132159	uncertain significance	Neuronal ceroid lipofuscinosis 8	2016-07-21	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001580081	SCV001809606	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001580081	SCV001927180	pathogenic	not provided		no assertion criteria provided	clinical testing