Submissions for variant NM_004937.3(CTNS):c.694C>T (p.Arg232Cys)

gnomAD frequency: 0.00011  dbSNP: rs138823792

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000260063	SCV000402233	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	RCV000319800	SCV000402234	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	RCV002495016	SCV002786385	uncertain significance	Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis	2021-07-07	criteria provided, single submitter	clinical testing
Invitae	RCV002522941	SCV003264894	uncertain significance	Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases	2022-03-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 232 of the CTNS protein (p.Arg232Cys). This variant is present in population databases (rs138823792, gnomAD 0.03%). 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: 322841). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV002522940	SCV003529708	uncertain significance	Inborn genetic diseases	2021-10-06	criteria provided, single submitter	clinical testing	The c.694C>T (p.R232C) alteration is located in exon 10 (coding exon 8) of the CTNS gene. This alteration results from a C to T substitution at nucleotide position 694, causing the arginine (R) at amino acid position 232 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.