Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001378313 | SCV001575858 | pathogenic | Neuronal ceroid lipofuscinosis | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 103 of the CLN6 protein (p.Arg103Gln). This variant is present in population databases (rs154774634, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of neuronal ceroid lipofuscinosis (PMID: 21549341, 30561534, 35505348). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30600). 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 with a negative predictive value of 80%. This variant disrupts the p.Arg103 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18846690, 27903347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Revvity Omics, |
RCV000058911 | SCV002023254 | likely pathogenic | not provided | 2021-10-15 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001378313 | SCV002103923 | likely pathogenic | Neuronal ceroid lipofuscinosis | 2022-02-02 | criteria provided, single submitter | clinical testing | Variant summary: CLN6 c.308G>A (p.Arg103Gln, p.R103Q) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250396 control chromosomes (gnomAD). c.308G>A has been reported in the literature in compound heterozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and this variant was co-segregated with disease (example: Arsov_ 2011, Berkovic_2019). These data indicate that the variant is likely to be associated with disease. Additionally, another missense variant at the same codon, R103W, has been found in patients with Neuronal Ceroid-Lipofuscinosis in the Human Gene Mutation Database, indicating the arginine residue is critical for CLN6 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant likely pathogenic (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| OMIM | RCV001787031 | SCV000044864 | pathogenic | Ceroid lipofuscinosis, neuronal, 6B (Kufs type) | 2011-05-13 | no assertion criteria provided | literature only | |
| SNPedia | RCV000058911 | SCV000090432 | not provided | not provided | no assertion provided | not provided | ||
| Counsyl | RCV000675061 | SCV000800520 | uncertain significance | Ceroid lipofuscinosis, neuronal, 6A | 2017-05-01 | flagged submission | clinical testing |