Submissions for variant NM_001042432.2(CLN3):c.1054C>T (p.Gln352Ter)

gnomAD frequency: 0.00002  dbSNP: rs386833697

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000579238	SCV000680509	pathogenic	not provided	2017-10-10	criteria provided, single submitter	clinical testing	The Q352X nonsense variant in the CLN3 gene has been reported previously in association with juvenile neuronal ceroid lipofucinosis (Munroe et al., 1997, Miller et al., 2013). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q352X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this nonsense variant is considered to be a pathogenic variant.
Genome-Nilou Lab	RCV000049658	SCV001977441	pathogenic	Neuronal ceroid lipofuscinosis 3	2021-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804785	SCV002051191	pathogenic	Neuronal ceroid lipofuscinosis	2021-12-17	criteria provided, single submitter	clinical testing	Variant summary: CLN3 c.1054C>T (p.Gln352X) 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. The variant allele was found at a frequency of 8.1e-06 in 245602 control chromosomes (gnomAD). c.1054C>T has been reported in the literature in multiple individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease) (examples: Munroe_1997, Miller_2013, Kousi_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence, and demonstrated that the CLN3 mRNA level was decreased in LCLs derived from a homozygous patient, presumably due to nonsense mediated decay (Miller_2013). Three ClinVar submitter have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001804785	SCV002241056	pathogenic	Neuronal ceroid lipofuscinosis	2023-05-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 56246). This premature translational stop signal has been observed in individual(s) with CLN3-related conditions (PMID: 9311735, 23539563). This variant is present in population databases (rs386833697, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Gln352*) 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).
Baylor Genetics	RCV000049658	SCV004214307	pathogenic	Neuronal ceroid lipofuscinosis 3	2024-01-25	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049658	SCV000082065	probable-pathogenic	Neuronal ceroid lipofuscinosis 3		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Counsyl	RCV000049658	SCV000798303	pathogenic	Neuronal ceroid lipofuscinosis 3	2018-03-06	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000579238	SCV001922197	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000579238	SCV001973063	pathogenic	not provided		no assertion criteria provided	clinical testing