Submissions for variant NM_004937.3(CTNS):c.18_21del (p.Thr7fs)

dbSNP: rs786204501

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169183	SCV000220424	pathogenic	Nephropathic cystinosis	2014-06-17	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000723831	SCV000229059	pathogenic	not provided	2015-04-24	criteria provided, single submitter	clinical testing
Invitae	RCV002516530	SCV000827371	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr7Phefs*7) 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 (rs764835663, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with nephropathic cystinosis (PMID: 9537412, 28276207). ClinVar contains an entry for this variant (Variation ID: 188834). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000258029	SCV000917266	pathogenic	Cystinosis	2018-01-29	criteria provided, single submitter	clinical testing	Variant summary: CTNS c.18_21delGACT (p.Thr7PhefsX7) 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 (eg. c.646dupA/p.Thr216fsX12). The variant allele was found at a frequency of 5.4e-05 in 277224 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CTNS causing Cystinosis (5.4e-05 vs 0.0025). c.18_21delGACT has been reported in the literature in multiple individuals affected with Cystinosis. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000698691	SCV001163422	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000723831	SCV001249975	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV000169183	SCV001425072	pathogenic	Nephropathic cystinosis	2020-02-01	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000723831	SCV002019770	pathogenic	not provided	2020-05-26	criteria provided, single submitter	clinical testing
Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	RCV001843488	SCV002102788	pathogenic	Infantile nephropathic cystinosis	2022-03-07	criteria provided, single submitter	clinical testing
3billion	RCV000169183	SCV002318731	pathogenic	Nephropathic cystinosis	2022-03-22	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000188834, PMID:9537412). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000594). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000698691	SCV002809365	pathogenic	Ocular cystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis	2021-07-26	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000169183	SCV004100570	pathogenic	Nephropathic cystinosis		criteria provided, single submitter	clinical testing	The frameshift deletion p.T7Ffs*7 in CTNS (NM_004937.3) has been observed as homozygous or in combination with another CTNS variant in individuals and families affected with nephropathic cystinosis (Town M et al; Onenli et al). The variant has been reported to ClinVar as Pathogenic. The p.T7Ffs*7 variant is observed in 4/30,612 (0.0131%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The p.T7Ffs*7 variant is a loss of function variant in the gene CTNS, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_004928.2:p.T7Ffs*7 and 26 others. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169183	SCV004212929	pathogenic	Nephropathic cystinosis	2023-10-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917579	SCV004728093	pathogenic	CTNS-related condition	2023-11-17	criteria provided, single submitter	clinical testing	The CTNS c.18_21delGACT variant is predicted to result in a frameshift and premature protein termination (p.Thr7Phefs*7). This variant, also referred to as 357delGACT, has been reported in the homozygous and compound heterozygous state in cystinosis patients (e.g., Town et al. 1998. PubMed ID: 9537412; Macías-Vidal et al. 2009. PubMed ID: 19863563; Ghazi et al. 2017. PubMed ID: 28238446). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org). Frameshift variants in CTNS are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000169183	SCV000024869	pathogenic	Nephropathic cystinosis	2009-11-01	no assertion criteria provided	literature only
OMIM	RCV000004695	SCV000024870	pathogenic	Juvenile nephropathic cystinosis	2009-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000258029	SCV000328206	not provided	Cystinosis		no assertion provided	literature only
Natera, Inc.	RCV000258029	SCV001463143	pathogenic	Cystinosis	2020-09-16	no assertion criteria provided	clinical testing