Submissions for variant NM_018941.4(CLN8):c.709G>A (p.Gly237Arg)

gnomAD frequency: 0.00001  dbSNP: rs746645358

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169279	SCV000220586	likely pathogenic	Neuronal ceroid lipofuscinosis 8	2014-08-12	criteria provided, single submitter	literature only
GeneDx	RCV000187126	SCV000240702	likely pathogenic	not provided	2017-07-06	criteria provided, single submitter	clinical testing	The Gly237Arg missense variant in the CLN8 gene has been previously reported as a homozygous variant in two individuals with a clinical phenotype suggestive of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) (Reinhardt et al., 2010). Gly237Arg is a non-conservative amino acid substitution as a uncharged non-polar Glycine residue is replaced by a positively charged Arginine residue. In addition, Gly237Arg alters a conserved position in the fifth transmembrane domain of the CLN8 protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169279	SCV001623387	pathogenic	Neuronal ceroid lipofuscinosis 8	2023-03-07	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000187126	SCV002023255	likely pathogenic	not provided	2019-08-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003532006	SCV004294541	likely pathogenic	Neuronal ceroid lipofuscinosis	2023-06-20	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 188917). This missense change has been observed in individuals with neuronal ceroid lipofuscinosis (PMID: 19201763, 19807737, 21990111, 33358637). This variant is present in population databases (rs746645358, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 237 of the CLN8 protein (p.Gly237Arg).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000169279	SCV005016557	pathogenic	Neuronal ceroid lipofuscinosis 8	2024-03-14	criteria provided, single submitter	clinical testing