Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001235065 | SCV001407729 | likely pathogenic | Neuronal ceroid lipofuscinosis | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 259 of the CLN6 protein (p.Gly259Ser). This variant is present in population databases (rs150363441, gnomAD 0.01%). This missense change has been observed in individuals with neuronal ceroid lipofuscinosis (PMID: 21990111, 35505348; Invitae). ClinVar contains an entry for this variant (Variation ID: 961382). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLN6 protein function. This variant disrupts the p.Gly259 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 19135028, 31489614), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Foundation for Research in Genetics and Endocrinology, |
RCV001375037 | SCV001571713 | likely pathogenic | Ceroid lipofuscinosis, neuronal, 6A | 2021-02-12 | criteria provided, single submitter | clinical testing | A homozygous missense variant in exon 7 of the CLN6 gene that results in the amino acid substitution of Serine for Glycine at codon 259 was detected. The observed variant c.775G>A (p.Leu83Val) has not been reported in the 1000 genomes and has a MAF of 0.0024% in gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. |
Gene |
RCV001561994 | SCV001784694 | uncertain significance | not provided | 2020-02-24 | criteria provided, single submitter | clinical testing | Identified in a patient with suspected mitochondrial disease who also had a second CLN6 variant in trans (DaRe et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Different missense changes at this residue (G259C; G259V; G259D) reported in association with NCL in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24215330, 21990111) |
Mendelics | RCV002246224 | SCV002518720 | pathogenic | Ceroid lipofuscinosis, neuronal, 6B (Kufs type) | 2022-05-04 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002563820 | SCV003733100 | uncertain significance | Inborn genetic diseases | 2022-11-17 | criteria provided, single submitter | clinical testing | The c.775G>A (p.G259S) alteration is located in exon 7 (coding exon 7) of the CLN6 gene. This alteration results from a G to A substitution at nucleotide position 775, causing the glycine (G) at amino acid position 259 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |