ClinVar Miner

Submissions for variant NM_004937.3(CTNS):c.589G>A (p.Gly197Arg)

gnomAD frequency: 0.00004  dbSNP: rs113994207
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169004 SCV000220144 likely pathogenic Nephropathic cystinosis 2014-03-03 criteria provided, single submitter literature only
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000514820 SCV000609716 likely pathogenic not provided 2017-05-22 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763395 SCV000894116 likely pathogenic Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis 2022-04-08 criteria provided, single submitter clinical testing
Invitae RCV002512766 SCV000935698 pathogenic Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 197 of the CTNS protein (p.Gly197Arg). This variant is present in population databases (rs113994207, gnomAD 0.03%). This missense change has been observed in individual(s) with CTNS-related conditions (PMID: 10625078, 11505338, 28649545). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4451). 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 CTNS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTNS function (PMID: 15128704, 29467429). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844005 SCV002103764 pathogenic Cystinosis 2022-02-14 criteria provided, single submitter clinical testing Variant summary: CTNS c.589G>A (p.Gly197Arg) 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 5.6e-05 in 251352 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CTNS causing Cystinosis (5.6e-05 vs 0.0025), allowing no conclusion about variant significance. c.589G>A has been reported in the literature in multiple compound heterozygous individuals affected with Cystinosis (e.g. Anikster_2000, Kleta_2001, Phornphutkul_2001). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant confers low level of cystine transport and also, leads to a significant trafficking defect and is found to go to the cell surface (Kalatzis_2004, Deshpande_2018). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000169004 SCV004212944 pathogenic Nephropathic cystinosis 2023-09-26 criteria provided, single submitter clinical testing
OMIM RCV000004704 SCV000024879 pathogenic Ocular cystinosis 2000-01-01 no assertion criteria provided literature only
GeneReviews RCV000004704 SCV000041135 not provided Ocular cystinosis no assertion provided literature only

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.