Submissions for variant NM_004937.3(CTNS):c.454C>T (p.Arg152Trp)

gnomAD frequency: 0.00001  dbSNP: rs754433265

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001122889	SCV001281660	uncertain significance	Nephropathic cystinosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001122890	SCV001281661	uncertain significance	Ocular cystinosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics, Fulgent Genetics	RCV005093560	SCV002815705	uncertain significance	Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis	2022-02-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003413928	SCV004107165	uncertain significance	CTNS-related disorder	2022-11-10	criteria provided, single submitter	clinical testing	The CTNS c.454C>T variant is predicted to result in the amino acid substitution p.Arg152Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-3558639-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005225237	SCV005864788	uncertain significance	Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases	2024-03-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 152 of the CTNS protein (p.Arg152Trp). This variant is present in population databases (rs754433265, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CTNS-related conditions. ClinVar contains an entry for this variant (Variation ID: 889140). 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%. 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.
Natera, Inc.	RCV001277961	SCV001464946	uncertain significance	Cystinosis	2020-08-13	no assertion criteria provided	clinical testing