Submissions for variant NM_004937.3(CTNS):c.414G>A (p.Trp138Ter)

gnomAD frequency: 0.00010  dbSNP: rs113994205

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723832	SCV000232215	pathogenic	not provided	2015-04-24	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000004693	SCV000494240	pathogenic	Nephropathic cystinosis	2016-06-27	criteria provided, single submitter	clinical testing	The known nonsense variant, c.414G>A (p.Trp138Ter) introduces a stop codon at position 138 leading to a truncated cystinosin protein. In affected individuals within the American population, this variant is relatively common (~10%) (Shotelersuk V et al., 1998; Town et al. 1998; McGowan-Jordan J et al.1999), indicating that the prevalence of this variant in affected individuals is significantly higher than in controls. Several loss-of-function pathogenic variants (nonsense, frameshift, splice-site) have been reported, including a nonsense variant further downstream in exon 11 (Kalatzis V and Antignac C, 2003), suggesting loss-of-function as a mechanism of disease. The variant is observed in population databases (ExAc, 1000 Genomes, ESP) a frequency below what is expected carrier rate based on disease prevalence. This substitution co-segregates with disease (Town et al. 1998, McGowan-Jordan J et al.1999). This variant has recently been classified as pathogenic by a reputable clinical laboratory (Emory). Therefore, this variant is best interpreted as a Pathogenic variant for nephropathic cystinosis. We have confirmed this finding in our laboratory using Sanger sequencing
Invitae	RCV002512763	SCV000751431	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp138*) in the CTNS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTNS are known to be pathogenic (PMID: 9537412, 27102039). This variant is present in population databases (rs113994205, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with cystinosis (PMID: 9537412, 9792862, 10482956). ClinVar contains an entry for this variant (Variation ID: 4443). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000630473	SCV000894115	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis	2022-02-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000004693	SCV001193987	pathogenic	Nephropathic cystinosis	2019-12-20	criteria provided, single submitter	clinical testing	NM_004937.2(CTNS):c.414G>A(W138*) is classified as pathogenic in the context of cystinosis. Sources cited for classification include the following: PMID 9792862, 10482956 and 11855931. Classification of NM_004937.2(CTNS):c.414G>A(W138*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
GeneDx	RCV000723832	SCV002576983	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9537412, 25525159, 9792862, 20301574)
Baylor Genetics	RCV000004693	SCV004212940	pathogenic	Nephropathic cystinosis	2023-10-10	criteria provided, single submitter	clinical testing
OMIM	RCV000004693	SCV000024868	pathogenic	Nephropathic cystinosis	1999-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000004693	SCV000041133	not provided	Nephropathic cystinosis		no assertion provided	literature only
Natera, Inc.	RCV001276658	SCV001463148	pathogenic	Cystinosis	2020-09-16	no assertion criteria provided	clinical testing