ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.304G>A (p.Glu102Lys) (rs796052352)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187093 SCV000240668 uncertain significance not provided 2016-09-27 criteria provided, single submitter clinical testing The E102K 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 E102K 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 predicted that is conserved across species, and missense variants in nearby residues (R103W, R103Q, S104F) have been reported in the Human Gene Mutation Database in association with neuronal ceroid lipofuscinosis (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Counsyl RCV000666497 SCV000790802 uncertain significance Neuronal ceroid lipofuscinosis 6 2017-04-10 criteria provided, single submitter clinical testing
Invitae RCV001228807 SCV001401225 uncertain significance Neuronal ceroid lipofuscinosis 2019-08-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 102 of the CLN6 protein (p.Glu102Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CLN6-related conditions. ClinVar contains an entry for this variant (Variation ID: 205165). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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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