Submissions for variant NM_001042432.2(CLN3):c.954_962+18del

dbSNP: rs386833741

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001035044	SCV001198352	pathogenic	Neuronal ceroid lipofuscinosis	2023-12-23	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 13 (c.954_962+18del) of the CLN3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CLN3 are known to be pathogenic (PMID: 9311735, 28542676). This variant is present in population databases (rs386833741, gnomAD 0.002%). This variant has been observed in individuals with CLN3-related conditions (PMID: 21990111). ClinVar contains an entry for this variant (Variation ID: 56293). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001035044	SCV002051192	likely pathogenic	Neuronal ceroid lipofuscinosis	2021-12-17	criteria provided, single submitter	clinical testing	Variant summary: CLN3 c.954_962+18del27 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 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 248612 control chromosomes (gnomAD). c.954_962+18del27 has been reported in the literature in individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease) (examples: Kwon_2011 and Pronicka_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002381352	SCV002693690	pathogenic	Inborn genetic diseases	2020-02-12	criteria provided, single submitter	clinical testing	The c.954_962+18del27 pathogenic mutation results from a deletion of 27 nucleotides spanning across the splice donor site after coding exon 12 in the CLN3 gene. This mutation was detected in an individual with a diagnosis of Batten disease who had another pathogenic mutation on the other chromosome. In addition, this mutation was detected in three individuals with neuronal ceroid lipofuscinosis, two of whom had a second pathogenic mutation (the phase is unknown) (Kousi M et al. Hum. Mutat., 2012 Jan;33:42-63). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV003326342	SCV004033473	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	CLN3: PVS1, PM2, PM3
Baylor Genetics	RCV000049705	SCV004214322	pathogenic	Neuronal ceroid lipofuscinosis 3	2023-11-07	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049705	SCV000082112	probable-pathogenic	Neuronal ceroid lipofuscinosis 3		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.