Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000670264 | SCV000795097 | uncertain significance | Ceroid lipofuscinosis, neuronal, 6A | 2017-10-27 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000689116 | SCV000816754 | likely pathogenic | Neuronal ceroid lipofuscinosis | 2023-11-06 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 62 of the CLN6 protein (p.Arg62Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 19135028, 31216804). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554596). 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.Arg62 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 12815591), 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. |
| 3billion | RCV000670264 | SCV002012076 | likely pathogenic | Ceroid lipofuscinosis, neuronal, 6A | 2021-10-02 | criteria provided, single submitter | clinical testing | It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00000795, PM2). The variant was observed to be in trans with a pathogenic variant (NM_017882.2: c.307C>T) as compound heterozygous (3billion dataset). A different missense change at the same codon (p.Arg62His) has been reported as pathogenic (ClinVar ID: VCV000523022.2 PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.926, 3Cnet: 0.926, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |