ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.11C>T (p.Thr4Met) (rs1017662486)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482919 SCV000570048 uncertain significance not provided 2018-04-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CLN6 gene. The T4M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 2,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T4M 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. Additionally, missense variants in nearby residues (R5W, R6T) have been reported in the Human Gene Mutation Database in association with neuronal ceroid lipofuscinosis (Stenson et al., 2014). However, this substitution occurs at a position that is not conserved. 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 RCV001304989 SCV001494297 uncertain significance Neuronal ceroid lipofuscinosis 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 4 of the CLN6 protein (p.Thr4Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with CLN6-related conditions. ClinVar contains an entry for this variant (Variation ID: 420988). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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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