Submissions for variant NM_004937.3(CTNS):c.206_210del (p.Ile69fs)

dbSNP: rs879758262

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527666	SCV000625760	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile69Argfs*5) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cystinosis (PMID: 10625078). ClinVar contains an entry for this variant (Variation ID: 455787). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358753	SCV001554609	pathogenic	Cystinosis	2021-03-30	criteria provided, single submitter	clinical testing	Variant summary: CTNS c.206_210delTCCTT (p.Ile69ArgfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251456 control chromosomes. c.206_210delTCCTT has been reported as a homozygous mutation in at least one individual affected with Cystinosis (e.g. Shotelersuk_1998). These data indicate that the variant may be associated with disease. Fibroblasts from this patient were assessed as having higher levels of intracellular cystine compared to normal controls (e.g. Vitcitsky_2010). One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000004703	SCV004215227	pathogenic	Nephropathic cystinosis	2022-06-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005091262	SCV005641898	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis	2023-12-29	criteria provided, single submitter	clinical testing
OMIM	RCV000004703	SCV000024878	pathogenic	Nephropathic cystinosis	1998-11-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004730977	SCV005339637	pathogenic	CTNS-related disorder	2024-05-29	no assertion criteria provided	clinical testing	The CTNS c.206_210del5 variant is predicted to result in a frameshift and premature protein termination (p.Ile69Argfs*5). This variant has been reported in the hemizygous and compound heterozygous states in two individuals with cystinosis (Shotelersuk et al. 1998. PubMed ID: 9792862 with genotype corrected in Zykovich et al. 2015. PubMed ID: 28649545; Anikster et al. 1999. PubMed ID: 10625078). In vitro functional studies using cultured patient fibroblasts hemizygous for the p.Ile69Argfs*5 variant (with a 57 kb deletion of CTNS exons 1-10 on the opposite allele) detected an approximately 10X increase of intracellular cysteine in patient fibroblasts relative to wild type (Vitvitsky et al. 2010. PubMed ID: 20061170 with genotype corrected in Zykovich et al. 2015. PubMed ID: 28649545). This variant has not been reported in the gnomAD database, indicating this variant is rare. Frameshift variants in CTNS are expected to be pathogenic. This variant is interpreted as pathogenic.