ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.665+1G>A (rs796052356)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187100 SCV000240675 pathogenic not provided 2014-05-05 criteria provided, single submitter clinical testing c.665+1 G>A: IVS6+1 G>A in intron 6 of the CLN6 gene (NM_017882.2). The c.665+1 G>A splice site mutation in the CLN6 gene destroys the canonical splice donor site in intron 6. This mutation is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although this mutation has not been previously reported to our knowledge, homozygosity for this mutation is consistent with a diagnosis of neuronal ceroid lipofuscinosis (NCL). The variant is found in EPILEPSY panel(s).
Invitae RCV001379342 SCV001577128 likely pathogenic Neuronal ceroid lipofuscinosis 2020-02-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 6) of the CLN6 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CLN6-related conditions. ClinVar contains an entry for this variant (Variation ID: 205171). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Met241 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12815591, 18811591, 20430023, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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