Submissions for variant NM_001042432.2(CLN3):c.883G>T (p.Glu295Ter)

dbSNP: rs121434286

Total submissions: 7

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	2024-01-11	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. Loss-of-function variants in CLN3 are known to be pathogenic (PMID: 9311735, 28542676). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinal degeneration (PMID: 28542676). ClinVar contains an entry for this variant (Variation ID: 56290). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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)
Genome-Nilou Lab	RCV000049702	SCV001977443	pathogenic	Neuronal ceroid lipofuscinosis 3	2021-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000049702	SCV004214306	pathogenic	Neuronal ceroid lipofuscinosis 3	2023-10-20	criteria provided, single submitter	clinical testing
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.