ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.461-3C>G (rs181995380)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483799 SCV000571714 uncertain significance not provided 2016-09-21 criteria provided, single submitter clinical testing The c.461-3 C>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.461-3 C>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Several in-silico splice prediction models predict that c.461-3 C>G may damage or destroy the natural splice acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We interpret c.461-3 C>G as a variant of uncertain significance.
Invitae RCV001060717 SCV001225421 pathogenic Neuronal ceroid lipofuscinosis 2019-12-30 criteria provided, single submitter clinical testing This sequence change falls in intron 7 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 individual(s) with clinical features of retinitis pigmentosa (PMID: 28542676, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 422288). 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 disrupts mRNA splicing (PMID: 28542676). For these reasons, this variant has been classified as Pathogenic.

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