Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000534403 | SCV000628971 | pathogenic | Neuronal ceroid lipofuscinosis | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 5 of the CLN6 protein (p.Arg5Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111, 28831385, 33024953). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 457969). 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%. For these reasons, this variant has been classified as Pathogenic. |
| Counsyl | RCV000665418 | SCV000789538 | uncertain significance | Ceroid lipofuscinosis, neuronal, 6A | 2017-02-08 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330752 | SCV004037835 | uncertain significance | not specified | 2023-08-31 | criteria provided, single submitter | clinical testing | Variant summary: CLN6 c.13C>T (p.Arg5Trp) results in a non-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 2.5e-05 in 80612 control chromosomes (gnomAD). c.13C>T has been reported in the literature in the compound heterozygous state together with a VUS in three siblings with clinical features of Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Vairo_2017), in trans with a pathogenic variant an individual who underwent whole genome sequencing, confirming a diagnosis of Kufs disease/Neuronal Ceroid-Lipofuscinosis (Talbot_2020), and in the heterozygous state in at least one other affected individual (Kousi_2012). These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21990111, 33024953, 28831385). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Mayo Clinic Laboratories, |
RCV000675966 | SCV000801695 | uncertain significance | not provided | 2017-06-07 | no assertion criteria provided | clinical testing |