Submissions for variant NM_004937.3(CTNS):c.414G>A (p.Trp138Ter) (rs113994205)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	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	RCV000630473	SCV000751431	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis	2019-12-16	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. This variant is present in population databases (rs113994205, ExAC 0.006%). This variant has been reported in multiple individuals and families affected with cystinosis (PMID: 9537412, 10482956, 9792862). ClinVar contains an entry for this variant (Variation ID: 4443). Experimental studies have shown that this missense change results in no detectable protein (PMID: 11855931). Loss-of-function variants in CTNS are known to be pathogenic (PMID: 9537412, 27102039). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000630473	SCV000894115	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis	2018-10-31	criteria provided, single submitter	clinical testing
Myriad Women's Health, 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.
OMIM	RCV000004693	SCV000024868	pathogenic	Nephropathic cystinosis	1999-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000004693	SCV000041133	pathologic	Nephropathic cystinosis	2011-08-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Natera, Inc.	RCV001276658	SCV001463148	pathogenic	Cystinosis	2020-09-16	no assertion criteria provided	clinical testing