ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.1056+3A>C (rs386833698)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000819629 SCV000960300 likely pathogenic Neuronal ceroid lipofuscinosis 2018-12-24 criteria provided, single submitter clinical testing This sequence change falls in intron 14 of the CLN3 gene. It does not directly change the encoded amino acid sequence of the CLN3 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with juvenile neuronal ceroid lipofuscinosis (PMID: 24271013). This variant has also been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual with signs and symptoms indicative of neuronal ceroid lipofucinosis (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 56247). Experimental studies in iPSC cell lines derived from patient fibroblasts have shown that the late endosomal–lysosomal compartment is disrupted in CLN3 iPSCs. In addition, neurons from CLN3 affected individuals show progressive organellar pathology and characteristic NCL storage material (PMID: 24271013). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant leads to abnormal splicing (PMID: 24271013). 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.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049659 SCV000082066 probable-pathogenic Juvenile neuronal ceroid lipofuscinosis no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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