Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
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 | 2022-10-25 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 240 of the CLN6 protein (p.Ala240Thr). This variant is present in population databases (rs779105796, gnomAD 0.006%). 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: 420280). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLN6 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. |
| Ambry Genetics | RCV002376874 | SCV002670152 | uncertain significance | Inborn genetic diseases | 2018-09-29 | criteria provided, single submitter | clinical testing | The p.A240T variant (also known as c.718G>A), located in coding exon 7 of the CLN6 gene, results from a G to A substitution at nucleotide position 718. The alanine at codon 240 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |