ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.1012C>T (p.Arg338Cys) (rs776725094)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479432 SCV000570814 uncertain significance not provided 2016-07-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CLN3 gene. The R338C 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 R338C 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. Missense variants in a nearby residue (R334C, R334H) have been reported in the Human Gene Mutation Database in association with NCL (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved, and Cysteine is observed at this position in evolution. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000819028 SCV000959669 uncertain significance Neuronal ceroid lipofuscinosis 2018-07-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 338 of the CLN3 protein (p.Arg338Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs776725094, ExAC 0.03%). This variant has not been reported in the literature in individuals with CLN3-related disease. ClinVar contains an entry for this variant (Variation ID: 421563). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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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