ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs121908127
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Total submissions: 10
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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
Invitae 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 2023-10-14 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003904807 SCV004725984 pathogenic CTNS-related condition 2024-02-15 criteria provided, single submitter 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.
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

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