NM_004937.3(CTNS):c.771_793del (p.Gly258fs) AND Nephropathic cystinosis

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Mar 3, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000984254.16

Allele description [Variation Report for NM_004937.3(CTNS):c.771_793del (p.Gly258fs)]

NM_004937.3(CTNS):c.771_793del (p.Gly258fs)

Gene:

CTNS:cystinosin, lysosomal cystine transporter [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17p13.2

Genomic location:

Preferred name:

NM_004937.3(CTNS):c.771_793del (p.Gly258fs)

HGVS:

NC_000017.11:g.3658094_3658116del
NG_012489.2:g.26627_26649del
NM_001031681.3:c.771_793del
NM_001374492.1:c.771_793del
NM_001374493.1:c.330_352del
NM_001374494.1:c.330_352del
NM_001374495.1:c.330_352del
NM_001374496.1:c.330_352del
NM_004937.3:c.771_793delMANE SELECT
NP_001026851.2:p.Gly258fs
NP_001026851.2:p.Gly258fs
NP_001361421.1:p.Gly258fs
NP_001361422.1:p.Gly111fs
NP_001361423.1:p.Gly111fs
NP_001361424.1:p.Gly111fs
NP_001361425.1:p.Gly111fs
NP_004928.2:p.Gly258fs
NC_000017.10:g.3561376_3561398del
NC_000017.10:g.3561388_3561410del
NM_001031681.2:c.771_793del
NM_004937.2:c.771_793del23
NM_004937.3:c.771_793del23MANE SELECT

Protein change:

G111fs

Links:

dbSNP: rs759623796

NCBI 1000 Genomes Browser:

rs759623796

Molecular consequence:

NM_001031681.3:c.771_793del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374492.1:c.771_793del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374493.1:c.330_352del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374494.1:c.330_352del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374495.1:c.330_352del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374496.1:c.330_352del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004937.3:c.771_793del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Nephropathic cystinosis (CTNS)
Synonyms:: CYSTINOSIN, DEFECT OF; LYSOSOMAL CYSTINE TRANSPORT PROTEIN, DEFECT OF; Abderhalden Lignac Kaufmann disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0100151; MedGen: C2931187; Orphanet: 213; Orphanet: 411629; OMIM: 219800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000698526	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 3, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10556299, 26266097 Citation Link,
SCV001132377	Counsyl	no assertion criteria provided	Likely pathogenic (Aug 16, 2014)	unknown	clinical testing
SCV001573147	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 26, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26266097, 25741868
SCV004215218	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 25, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004806437	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005329277	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin.

Attard M, Jean G, Forestier L, Cherqui S, van't Hoff W, Broyer M, Antignac C, Town M.

Hum Mol Genet. 1999 Dec;8(13):2507-14.

PubMed [citation]

PMID:: 10556299

Genetic basis of cystinosis in Tunisian patients: Identification of novel mutation in CTNS gene.

Chkioua L, Khedhiri S, Grissa O, Aloui C, Turkia HB, Ferchichi S, Miled A, Froissart R, Acquaviva C, Laradi S.

Meta Gene. 2015 Sep;5:144-9. doi: 10.1016/j.mgene.2015.07.003.

PubMed [citation]

PMID:: 26266097
PMCID:: PMC4528043

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698526.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: CTNS c.771_793del23 (p.Gly258SerfsX30) 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. The variant allele was found at a frequency of 2.8e-05 in 251296 control chromosomes. c.771_793del23 has been reported in the literature in individuals affected with Nephropathic cystinosis. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10556299, 26266097). ClinVar contains an entry for this variant (Variation ID: 496276). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV001132377.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV001573147.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This 23 bp deletion in CTNS has been previously reported in individuals with nephropathic cystinosis. This CTNS variant (rs759623796) is rare (<0.1%) in a large population dataset (gnomAD: 7/251296 total alleles; 0.003%; no homozygotes) and there is an entry in ClinVar. This frameshift variant results in a premature stop codon in exon 11 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004215218.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV004806437.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005329277.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The observed frameshift c.771_793del (p.Gly258SerfsTer30) variant in CTNS gene has been reported in homozygous state in individual(s) affected with cystinosis (Chkioua L et al., 2015; Ghazi F, et. al., 2017). The p.Gly258SerfsTer30 variant is present with allele frequency 0.003% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Glycine 258, changes this amino acid to Serine residue, and creates a premature Stop codon at position 30 of the new reading frame, denoted p.Gly258SerfsTer30. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in CTNS are known to be pathogenic (Elmonem MA, et. al., 2016). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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