Submissions for variant NM_001042432.2(CLN3):c.1198-1G>T

gnomAD frequency: 0.00001  dbSNP: rs386833702

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000049663	SCV000793509	pathogenic	Neuronal ceroid lipofuscinosis 3	2017-08-24	criteria provided, single submitter	clinical testing
Invitae	RCV001380722	SCV001578874	pathogenic	Neuronal ceroid lipofuscinosis	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 15 of the CLN3 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs386833702, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with juvenile neuronal ceroid lipofuscinosis (PMID: 9311735). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS14-1G>T. ClinVar contains an entry for this variant (Variation ID: 56251). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002336200	SCV002645171	likely pathogenic	Inborn genetic diseases	2018-11-30	criteria provided, single submitter	clinical testing	The c.1198-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 15 of the CLN3 gene. Alterations that disrupt the canonical splice site are typically deleterious in nature; however, this alteration occurs at the splice acceptor site of the last intron of CLN3 and is not expected to trigger nonsense-mediated mRNA decay. This variant was detected in three affected siblings with juvenile-onset neuronal ceroid lipofuscinosis, who had a common deletions of exons 7 and 8 (c.461-280_677+382del) on the other chromosome (Munroe PB et al. Am. J. Hum. Genet., 1997 Aug;61:310-6). RT-PCR analysis in one of the siblings revealed that this alteration activated a cryptic splice acceptor site in exon 15, resulting in introduction of a premature stop codon. In addition, a likely pathogenic variant (p.D416G) in the last exon has been reported in multiple affected individuals (Kwon JM et al. Neurology, 2011 Nov;77:1801-7; Lojewski X et al. Hum. Mol. Genet., 2014 Apr;23:2005-22), suggesting functional importance of amino acids affected by the premature stop codon. Based on data from gnomAD, the T allele has an overall frequency of approximately 0.0008% (2/250410). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is also predicted to abolish the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001380722	SCV004122117	pathogenic	Neuronal ceroid lipofuscinosis	2023-10-25	criteria provided, single submitter	clinical testing	Variant summary: CLN3 c.1198-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. Three predict the variant creates or strengthens a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Munroe_1997), resulting in the use of a cryptic splice acceptor site and a premature stop codon. The variant allele was found at a frequency of 8e-06 in 250410 control chromosomes (gnomAD). c.1198-1G>T has been reported in the literature in related individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) who were compound heterozygous with a pathogenic large deletion change (Munroe_1997). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 9311735). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049663	SCV000082070	probable-pathogenic	Neuronal ceroid lipofuscinosis 3		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.