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

gnomAD frequency: 0.00004  dbSNP: rs113994207

Total submissions: 8

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	2024-03-30	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