ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.868G>T (p.Val290Leu) (rs369008702)

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Total submissions: 2
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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.
Invitae RCV000696008 SCV000824549 uncertain significance Neuronal ceroid lipofuscinosis 2018-07-18 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 290 of the CLN3 protein (p.Val290Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs369008702, ExAC 0.001%). This variant has been observed to segregate with autosomal recessive retinitis pigmentosa in a family (PMID: 24154662). ClinVar contains an entry for this variant (Variation ID: 205083). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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