ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.482C>T (p.Thr161Met) (rs757734645)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519270 SCV000621065 uncertain significance not provided 2017-09-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CLN6 gene. The T161M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T161M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The T161M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position where amino acids with similar properties to Threonine are tolerated across species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000632709 SCV000753895 uncertain significance Neuronal ceroid lipofuscinosis 2018-01-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 161 of the CLN6 protein (p.Thr161Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs757734645, ExAC 0.005%). This variant has not been reported in the literature in individuals with CLN6-related disease. 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 C15"). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768186 SCV000898617 uncertain significance Neuronal ceroid lipofuscinosis 6; Adult neuronal ceroid lipofuscinosis 2017-11-30 criteria provided, single submitter clinical testing CLN6 NM_017882.2 exon 4 p.Thr161Met (c.482C>T): This variant has not been reported in the literature but is present in 4/111698 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs757734645). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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