ClinVar Miner

Submissions for variant NM_001042432.2(CLN3):c.868G>T (p.Val290Leu)

dbSNP: rs369008702
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187004 SCV000240577 uncertain significance not provided 2017-11-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CLN3 gene. The V290L variant has been reported previously in two siblings with retinitis pigmentosa who also carried a nonsense variant in CLN3; however, neitherindividual reported any signs of Batten disease (Wang et al., 2014). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The V290L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally,in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000696008 SCV000824549 pathogenic Neuronal ceroid lipofuscinosis 2023-11-28 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 290 of the CLN3 protein (p.Val290Leu). This variant is present in population databases (rs369008702, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of retinitis pigmentosa (PMID: 24154662, 33507216; Invitae). ClinVar contains an entry for this variant (Variation ID: 205083). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLN3 protein function with a negative predictive value of 80%. 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.
Genome-Nilou Lab RCV001785494 SCV002027101 uncertain significance Neuronal ceroid lipofuscinosis 3 2021-09-05 criteria provided, single submitter clinical testing
Natera, Inc. RCV000696008 SCV001452332 uncertain significance Neuronal ceroid lipofuscinosis 2020-09-16 no assertion criteria provided clinical testing

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