Submissions for variant NM_004937.3(CTNS):c.681G>A (p.Glu227=)

dbSNP: rs778414542

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668750	SCV000793400	pathogenic	Nephropathic cystinosis	2017-08-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531208	SCV001591757	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases	2021-07-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site, which introduces a premature termination codon (PMID: 19852576). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 553330). This variant has been observed in individuals with cystinosis (PMID: 19852576, 21786142). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 227 of the CTNS mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CTNS protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001543503	SCV001762115	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
3billion	RCV000668750	SCV003841997	pathogenic	Nephropathic cystinosis	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 19852576). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.80). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23640116 / 19852576‚Äö21786142). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000553330). 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	RCV000668750	SCV004031449	pathogenic	Nephropathic cystinosis	2023-09-04	criteria provided, single submitter	clinical testing	In-Silico PredictorsPP3: Pathogenic Strong
Baylor Genetics	RCV000668750	SCV004212946	pathogenic	Nephropathic cystinosis	2023-09-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001543503	SCV005042527	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	CTNS: PVS1, PM3:Strong, PM2, PP4:Moderate
Natera, Inc.	RCV001829850	SCV002093232	pathogenic	Cystinosis	2021-10-19	no assertion criteria provided	clinical testing