ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.1033A>T (p.Thr345Ser) (rs150986176)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000316657 SCV000396323 uncertain significance Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000482097 SCV000567921 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CLN3 gene. The T345S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T345S variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved in mammals. However, the T345S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the 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 RCV000560850 SCV000628921 uncertain significance Neuronal ceroid lipofuscinosis 2017-03-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 345 of the CLN3 protein (p.Thr345Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs150986176, ExAC 0.007%) but has not been reported in the literature in individuals with a CLN3-related disease. ClinVar contains an entry for this variant (Variation ID: 318718). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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