ClinVar Miner

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

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Total submissions: 8
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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

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