Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genomic Research Center, |
RCV000626225 | SCV000746871 | pathogenic | Ceroid lipofuscinosis, neuronal, 6A | 2017-12-18 | criteria provided, single submitter | clinical testing | |
Invitae | RCV002529782 | SCV003459461 | uncertain significance | Neuronal ceroid lipofuscinosis | 2022-01-14 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 62 of the CLN6 protein (p.Arg62His). This variant is present in population databases (rs751486476, gnomAD 0.0009%). This missense change has been observed in individual(s) with CLN6-related conditions (PMID: 12815591). ClinVar contains an entry for this variant (Variation ID: 523022). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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: 19135028), which suggests that this may be a clinically significant amino acid residue. 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. |
Lifecell International Pvt. |
RCV003228965 | SCV003922414 | likely pathogenic | Ceroid lipofuscinosis, neuronal, 6B (Kufs type) | criteria provided, single submitter | clinical testing | A Homozygote Missense variant c.185G>A in Exon 2 of the CLN6 gene that results in the amino acid substitution p.Arg62His was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 523022]. The observed variation has been reported previously in patients with late infantile neuronal ceroid lipofuscinosis (Sun G, et.al., 2018). For these reasons, this variant has been classified as Likely Pathogenic. | |
Child Neurology Division, |
RCV000626225 | SCV000889948 | pathogenic | Ceroid lipofuscinosis, neuronal, 6A | 2019-03-06 | no assertion criteria provided | clinical testing | The identified variant has been previously reported in a familial case of NCL; however, evidence for the pathogenicity of this variant was not provided in this study. Sharp JD et al. 2003. Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis. Hum. Mutat. 22(1):35-42 |