ClinVar Miner

Submissions for variant NM_006493.4(CLN5):c.286C>T (p.Arg96Ter) (rs386833971)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049947 SCV000221008 likely pathogenic Neuronal ceroid lipofuscinosis 5 2015-01-06 criteria provided, single submitter literature only
Invitae RCV001058589 SCV001223172 pathogenic Neuronal ceroid lipofuscinosis 2019-01-31 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CLN5 gene (p.Arg145*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 263 amino acids of the CLN5 protein. This variant is present in population databases (rs386833971, ExAC 0.01%). This variant has been observed in individuals affected with neuronal ceroid lipofuscinosis (PMID: 21990111). ClinVar contains an entry for this variant (Variation ID: 56534). This variant disrupts the C-terminus of the CLN5 protein. Other variant(s) that disrupt this region (p.Lys368Serfs*15 and p.Tyr392*) have been determined to be pathogenic (PMID: 22532218, 20157158, 20960652, 25976102, 9662406). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001058589 SCV001338110 likely pathogenic Neuronal ceroid lipofuscinosis 2020-01-24 criteria provided, single submitter clinical testing Variant summary: CLN5 c.433C>T (p.Arg145X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 251424 control chromosomes (gnomAD). c.433C>T has been reported in the literature in at least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease-Kousi_2012). 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 other ClinVar submitter (evaluation after 2014) cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049947 SCV000082356 probable-pathogenic Neuronal ceroid lipofuscinosis 5 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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