Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000494015 | SCV000582307 | uncertain significance | not provided | 2017-05-15 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the CLN6 gene. The I101V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I101V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I101V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense variants in nearby residues (K99N, R103W/Q, S104F) have been reported in the Human Gene Mutation Database in association with neuronal ceroid lipofuscinosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV002527085 | SCV003518964 | uncertain significance | Neuronal ceroid lipofuscinosis | 2022-05-07 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 101 of the CLN6 protein (p.Ile101Val). This variant is present in population databases (rs774238261, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CLN6-related conditions. ClinVar contains an entry for this variant (Variation ID: 429681). 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 valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |