Submissions for variant NM_001042432.2(CLN3):c.837+5G>A

gnomAD frequency: 0.00001  dbSNP: rs756848924

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000286126	SCV000396325	uncertain significance	Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000672125	SCV000797192	uncertain significance	Neuronal ceroid lipofuscinosis 3	2018-01-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001052203	SCV001216402	uncertain significance	Neuronal ceroid lipofuscinosis	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 of the CLN3 gene. It does not directly change the encoded amino acid sequence of the CLN3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs756848924, gnomAD 0.03%). This variant has been observed in individual(s) with isolated retinal degeneration (PMID: 28542676). ClinVar contains an entry for this variant (Variation ID: 318720). Variants that disrupt 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. 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.
Illumina Laboratory Services, Illumina	RCV000672125	SCV001275645	uncertain significance	Neuronal ceroid lipofuscinosis 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome-Nilou Lab	RCV000672125	SCV002027103	uncertain significance	Neuronal ceroid lipofuscinosis 3	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003278764	SCV003959380	uncertain significance	Inborn genetic diseases	2023-03-17	criteria provided, single submitter	clinical testing	The c.837+5G>A intronic alteration consists of a G to A substitution 5 nucleotides after exon 11 (coding exon 10) of the CLN3 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV000672125	SCV004171964	likely pathogenic	Neuronal ceroid lipofuscinosis 3		criteria provided, single submitter	clinical testing	The splice region c.837+5G>A variant in CLN3 gene has been reported previously in compound heterozygous state in an individual affected with Ceroid lipofuscinosis (Ku CA, et. al.,2017). The variant is reported with an allele frequency of 0.006% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain significance/ Likely pathogenic. SpliceAI predicts a donor loss of 0.64 for this variant. Loss of function variants have been previously reported to be disease causing. Functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504683	SCV000598889	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research