ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.883G>T (p.Glu295Ter) (rs121434286)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049702 SCV000793104 likely pathogenic Neuronal ceroid lipofuscinosis 3 2017-07-27 criteria provided, single submitter clinical testing
Invitae RCV001055217 SCV001219595 pathogenic Neuronal ceroid lipofuscinosis 2020-02-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu295*) in the CLN3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another CLN3 variant in an individual affected with retinal degeneration (PMID: 28542676). ClinVar contains an entry for this variant (Variation ID: 56290). Loss-of-function variants in CLN3 are known to be pathogenic (PMID: 9311735, 28542676). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001055217 SCV001519540 pathogenic Neuronal ceroid lipofuscinosis 2021-03-11 criteria provided, single submitter clinical testing Variant summary: CLN3 c.883G>T (p.Glu295X) 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 was absent in 251470 control chromosomes (gnomAD). c.883G>T has been reported in the literature in individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease) and isolated retinal degeneration (Zhong_2000, Kousi_2012, Bell_2011, Ku_2017, Turriff_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001552759 SCV001773508 pathogenic not provided 2020-10-08 criteria provided, single submitter clinical testing Identified in a patient with suspected JNCL who did not have a second identifiable CLN3 variant (Kousi et al., 2012); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21990111, 31741823, 28542676, 31568712, 30769084, 11339651, 25525159, 21228398)
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049702 SCV000082109 probable-pathogenic Neuronal ceroid lipofuscinosis 3 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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