Submissions for variant NM_004937.3(CTNS):c.1015G>A (p.Gly339Arg)

gnomAD frequency: 0.00004  dbSNP: rs121908127

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000004708	SCV000485611	pathogenic	Nephropathic cystinosis	2016-09-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512767	SCV001208174	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases	2024-01-07	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 339 of the CTNS protein (p.Gly339Arg). This variant is present in population databases (rs121908127, gnomAD 0.005%). This missense change has been observed in individuals with cystinosis (PMID: 11565547, 12204010, 12825071, 21786142, 23640116). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4455). 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). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193377	SCV001362153	pathogenic	Cystinosis	2019-09-16	criteria provided, single submitter	clinical testing	Variant summary: CTNS c.1015G>A (p.Gly339Arg) 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 3.2e-05 in 251256 control chromosomes (gnomAD). c.1015G>A has been reported in the literature in multiple compound heterozygote and homozygote individuals affected with Cystinosis (eg- Mason_2003, Rupar_2001). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001781181	SCV002019768	pathogenic	not provided	2021-04-28	criteria provided, single submitter	clinical testing
3billion	RCV000004708	SCV003841896	pathogenic	Nephropathic cystinosis	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Protein truncation variants are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12204010). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004455). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences	RCV000004708	SCV004031451	pathogenic	Nephropathic cystinosis	2023-09-03	criteria provided, single submitter	clinical testing	In-Silico PredictorsPP3: Pathogenic Strong
Baylor Genetics	RCV000004708	SCV004212934	pathogenic	Nephropathic cystinosis	2024-03-12	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001193377	SCV004848898	pathogenic	Cystinosis	2023-02-02	criteria provided, single submitter	clinical testing	The p.Gly339Arg variant in CTNS has been reported in >10 individuals with cystinosis and segregated with disease in 2 families (Shotelersuk 1998 PMID: 9792862, Rupar 2001 PMID: 11565547, Kalatzis 2002 PMID: 12442267, Kalatzis 2004 PMID: 15128704, Savostyanov 2022 PMID: 35571017). It was also identified in 0.006% (4/68046) of European chromosomes by gnomAD, v.3 (http://gnomad.broadinstitute.org), and is reported in ClinVar (Variation ID 4455). In vitro funtional studies support an impact on protein function, and leukocyte cystine levels measured in patients were markedly increased (Shotelersuk 1998 PMID: 9792862, Kalatzis 2002 PMID: 12442267, Kalatzis 2004 PMID: 15128704). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystinosis. ACMG/AMP criteria applied: PM3_VeryStrong , PS3, PP1_Moderate, PP3, PP4, PM2_Supporting.
OMIM	RCV000004708	SCV000024883	pathogenic	Nephropathic cystinosis	2001-09-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001193377	SCV001463155	pathogenic	Cystinosis	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904807	SCV004725984	pathogenic	CTNS-related disorder	2024-09-23	no assertion criteria provided	clinical testing	The CTNS c.1015G>A variant is predicted to result in the amino acid substitution p.Gly339Arg. This variant has been reported in the homozygous or compound heterozygous state with a second causative CTNS variant in multiple cystinosis patients (Attard et al. 1999. PubMed ID: 10556299; Rupar et al. 2001. PubMed ID: 11565547; Shahkarami et al. 2013. PubMed ID: 23640116; Soliman et al. 2014. PubMed ID: 24464559). The p.Gly339 amino acid is located in the seventh transmembrane domain of the cystinosin protein, and in an in vitro functional study this substitution was reported to abolish cysteine transport (Kalatzis et al. 2004. PubMed ID: 15128704). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.