ClinVar Genomic variation as it relates to human health
NM_004937.3(CTNS):c.473T>C (p.Leu158Pro)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004937.3(CTNS):c.473T>C (p.Leu158Pro)
Variation ID: 21439 Accession: VCV000021439.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 3656498 (GRCh38) [ NCBI UCSC ] 17: 3559792 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 3, 2013 Feb 28, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004937.3:c.473T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004928.2:p.Leu158Pro missense NM_001031681.3:c.473T>C NP_001026851.2:p.Leu158Pro missense NM_001374492.1:c.473T>C NP_001361421.1:p.Leu158Pro missense NM_001374493.1:c.32T>C NP_001361422.1:p.Leu11Pro missense NM_001374494.1:c.32T>C NP_001361423.1:p.Leu11Pro missense NM_001374495.1:c.32T>C NP_001361424.1:p.Leu11Pro missense NM_001374496.1:c.32T>C NP_001361425.1:p.Leu11Pro missense NC_000017.11:g.3656498T>C NC_000017.10:g.3559792T>C NG_012489.2:g.25031T>C O60931:p.Leu158Pro - Protein change
- L158P, L11P
- Other names
- -
- Canonical SPDI
- NC_000017.11:3656497:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CTNS | - | - |
GRCh38 GRCh37 |
501 | 904 | |
CTNS-AS1 | - | - | - | GRCh38 | - | 316 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2023 | RCV000020624.14 | |
Pathogenic (2) |
criteria provided, single submitter
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May 13, 2022 | RCV001276660.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 8, 2023 | RCV001781295.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 22, 2021 | RCV002243657.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2024 | RCV002513140.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystinosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002548350.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: CTNS c.473T>C (p.Leu158Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: CTNS c.473T>C (p.Leu158Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 247434 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CTNS causing Cystinosis (4e-05 vs 0.0025), allowing no conclusion about variant significance. c.473T>C has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Cystinosis (example, McGowan-Jordan_1999, Kalatzis_2004, Zykovich_2015, Ghazi_2017). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishment of cystine transport while not affecting the lysosomal localization of cystinosin (Kalatzis_2004). Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Ocular cystinosis
Nephropathic cystinosis Juvenile nephropathic cystinosis
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002778418.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002031051.2
First in ClinVar: Dec 12, 2021 Last updated: Mar 04, 2023 |
Comment:
Functional studies demonstrated that L158P allowed normal trafficking to the lysosomes, but that it abolished cystine transport (Kalatzis et al., 2004); Not observed at significant … (more)
Functional studies demonstrated that L158P allowed normal trafficking to the lysosomes, but that it abolished cystine transport (Kalatzis et al., 2004); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10482956, 21963264, 28238446, 12644911, 28649545, 34237326, 32198276, 15128704) (less)
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Likely pathogenic
(Aug 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Nephropathic cystinosis
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004099073.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
PS3, PM3
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Pathogenic
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Nephropathic cystinosis
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004211311.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Nov 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023435.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Ocular cystinosis Juvenile nephropathic cystinosis
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001205465.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 158 of the CTNS protein (p.Leu158Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 158 of the CTNS protein (p.Leu158Pro). This variant is present in population databases (rs113994206, gnomAD 0.008%). This missense change has been observed in individual(s) with cystinosis (PMID: 10482956, 28649545; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21439). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTNS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTNS function (PMID: 15128704). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Cystinosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001463150.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Nephropathic cystinosis
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000041134.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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CTNS molecular genetics profile in a Persian nephropathic cystinosis population. | Ghazi F | Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia | 2017 | PMID: 28238446 |
Cystinosis. | Adam MP | - | 2017 | PMID: 20301574 |
CTNS mutations in publicly-available human cystinosis cell lines. | Zykovich A | Molecular genetics and metabolism reports | 2015 | PMID: 28649545 |
Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. | Kalatzis V | Human molecular genetics | 2004 | PMID: 15128704 |
New aspects of the pathogenesis of cystinosis. | Kalatzis V | Pediatric nephrology (Berlin, Germany) | 2003 | PMID: 12644911 |
Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation. | McGowan-Jordan J | European journal of human genetics : EJHG | 1999 | PMID: 10482956 |
Text-mined citations for rs113994206 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.