ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.718G>A (p.Ala240Thr) (rs779105796)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480128 SCV000569048 uncertain significance not provided 2015-12-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CLN6 gene. The A240T 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 6,500 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 A240T 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. This substitution occurs at a position that is conserved in mammals and is predicted to be within the sixth transmembrane domain of the CLN6 protein (Kousi et al., 2012); however, Threonine is observed at this position in evolution. 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 RCV000529770 SCV000628982 uncertain significance Neuronal ceroid lipofuscinosis 2019-05-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 240 of the CLN6 protein (p.Ala240Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality 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: 420280). 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 threonine 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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