Submissions for variant NM_018941.4(CLN8):c.499G>T (p.Glu167Ter)

gnomAD frequency: 0.00004  dbSNP: rs144495588

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187127	SCV000240703	likely pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 120 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29655203, 31440721, 24077912, 26075876)
Genetic Services Laboratory, University of Chicago	RCV000503130	SCV000594158	pathogenic	Neuronal ceroid lipofuscinosis	2016-07-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000503130	SCV001198328	pathogenic	Neuronal ceroid lipofuscinosis	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu167*) in the CLN8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 120 amino acid(s) of the CLN8 protein. This variant is present in population databases (rs144495588, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 26075876). ClinVar contains an entry for this variant (Variation ID: 205194). This variant disrupts a region of the CLN8 protein in which other variant(s) (p.Leu188Valfs*58) have been determined to be pathogenic (PMID: 22220808; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002336495	SCV002641761	pathogenic	Inborn genetic diseases	2018-01-31	criteria provided, single submitter	clinical testing	The p.E167* pathogenic mutation (also known as c.499G>T), located in coding exon 1 of the CLN8 gene, results from a G to T substitution at nucleotide position 499. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This alteration was identified in the heterozygous state in an individual with a clinical diagnosis of neuronal lipofuscinosis (NCL) type 8, in addition, there was another suspected disease-causing alteration found in the individual as well (Di Fruscio G et al. Autophagy, 2015;11:928-38). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000665564	SCV003799090	likely pathogenic	Neuronal ceroid lipofuscinosis 8	2022-10-07	criteria provided, single submitter	clinical testing	PVS1, PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000503130	SCV005062088	pathogenic	Neuronal ceroid lipofuscinosis	2024-03-12	criteria provided, single submitter	clinical testing	Variant summary: CLN8 c.499G>T (p.Glu167X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. Variants downstream of this position have been classified as pathogenic by our laboratory (example, p.Arg204Cys, p.Gly237Arg). The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes. c.499G>T has been reported in the literature in at-least one individual affected with Neuronal Ceroid-Lipofuscinosis (example, Di Fruscio_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26075876). ClinVar contains an entry for this variant (Variation ID: 205194). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl	RCV000665564	SCV000789709	likely pathogenic	Neuronal ceroid lipofuscinosis 8	2017-02-14	no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000665564	SCV002030758	not provided	Neuronal ceroid lipofuscinosis 8		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 08-24-2021 by Lab or GTR ID 500031. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR ) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect.