ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000732347 SCV000565798 uncertain significance not provided 2018-01-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CLN3 gene. The c.461-3 C>A varianthas not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 8/31994 (0.03%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). Several in silico splice prediction models predict that c.461-3 C>A may weaken or destroy the natural splice acceptor site in intron 7 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.
Invitae RCV000692957 SCV000820809 uncertain significance Neuronal ceroid lipofuscinosis 2018-06-13 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 present in population databases (rs181995380, ExAC 0.03%). This variant has not been reported in the literature in individuals with CLN3-related disease. ClinVar contains an entry for this variant (Variation ID: 418607). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000732347 SCV000860296 uncertain significance not provided 2018-04-03 criteria provided, single submitter clinical testing

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