ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.776C>T (p.Pro259Leu) (rs137858807)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000173724 SCV000224872 uncertain significance not provided 2015-01-27 criteria provided, single submitter clinical testing
GeneDx RCV000173724 SCV000240608 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing The P259L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The 1000 Genomes Project reports P259L was observed in 2/198 (1.0%) alleles from individuals of Esan background in Nigeria. The P259L variant is a a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000173724 SCV000280836 uncertain significance not provided 2015-08-26 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Invitae RCV000532111 SCV000628939 uncertain significance Neuronal ceroid lipofuscinosis 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 259 of the CLN3 protein (p.Pro259Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs137858807, ExAC 0.1%). This variant has not been reported in the literature in individuals with CLN3-related disease. ClinVar contains an entry for this variant (Variation ID: 193616). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.