Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000049656 | SCV000220558 | likely pathogenic | Neuronal ceroid lipofuscinosis 3 | 2014-07-30 | criteria provided, single submitter | literature only | |
| Invitae | RCV000696638 | SCV000825206 | pathogenic | Neuronal ceroid lipofuscinosis | 2024-01-12 | 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 334 of the CLN3 protein (p.Arg334His). This variant is present in population databases (rs386833695, gnomAD 0.02%). This missense change has been observed in individuals with juvenile neuronal ceroid lipofuscinosis (PMID: 9311735, 20187884, 21499717, 21990111, 23539563). ClinVar contains an entry for this variant (Variation ID: 56244). 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 expected to disrupt CLN3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CLN3 function (PMID: 19132115, 23539563). This variant disrupts the p.Arg334 amino acid residue in CLN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9311735, 19132115, 21990111). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000049656 | SCV000917249 | pathogenic | Neuronal ceroid lipofuscinosis 3 | 2018-07-24 | criteria provided, single submitter | clinical testing | Variant summary: CLN3 c.1001G>A (p.Arg334His) results in a non-conservative amino acid change in the encoded protein sequence. Five 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 275154 control chromosomes (gnomAD and publications). The variant, c.1001G>A, has been reported in the literature in individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease)(Munroe_1997; Miller_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Haines_2009, Miller_2013). The most pronounced variant effect results in 10%-<30% of normal activity (Haskell_2000). Another variant at the same codon (p.R334C) has been associated with Juvenile Neuronal Ceroid-Lipofuscinosis, suggesting the codon is critical for protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000049656 | SCV004214304 | pathogenic | Neuronal ceroid lipofuscinosis 3 | 2024-03-21 | criteria provided, single submitter | clinical testing | |
| Juha Muilu Group; Institute for Molecular Medicine Finland |
RCV000049656 | SCV000082063 | probable-pathogenic | Neuronal ceroid lipofuscinosis 3 | no assertion criteria provided | not provided | Converted during submission to Likely pathogenic. |