ClinVar Genomic variation as it relates to human health
NM_004937.3(CTNS):c.422C>T (p.Ser141Phe)
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.422C>T (p.Ser141Phe)
Variation ID: 651886 Accession: VCV000651886.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 3655313 (GRCh38) [ NCBI UCSC ] 17: 3558607 (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 Aug 14, 2019 Feb 28, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004937.3:c.422C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004928.2:p.Ser141Phe missense NM_001031681.2:c.422C>T NM_001031681.3:c.422C>T NP_001026851.2:p.Ser141Phe missense NM_001374492.1:c.422C>T NP_001361421.1:p.Ser141Phe missense NM_001374493.1:c.-20C>T 5 prime UTR NM_001374494.1:c.-20C>T 5 prime UTR NM_001374495.1:c.-20C>T 5 prime UTR NM_001374496.1:c.-20C>T 5 prime UTR NC_000017.11:g.3655313C>T NC_000017.10:g.3558607C>T NG_012489.2:g.23846C>T - Protein change
- S141F
- Other names
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- Canonical SPDI
- NC_000017.11:3655312:C:T
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Oct 10, 2019 | RCV000807325.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 20, 2022 | RCV001816874.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 18, 2022 | RCV002509548.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV002537248.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2022 | RCV003338814.3 |
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
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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
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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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Likely pathogenic
(Oct 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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Nephropathic cystinosis
Juvenile nephropathic cystinosis Ocular cystinosis (Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology
Accession: SCV000999249.1
First in ClinVar: Nov 30, 2019 Last updated: Nov 30, 2019 |
Comment:
The Ser141Phe variant is not present in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC) however present in Genome … (more)
The Ser141Phe variant is not present in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC) however present in Genome Aggregation Database (gnomAD), dbSNP (rs1436441738) and our in-house exome database in heterozygous state at a very low frequency (MAF<0.0006). The variant was reported earlier to Human Genome Mutation Database (CM041752) in other similarly affected individuals [Kalatzis et al., Hum Mol Genet 2004]. In-silico pathogenicity prediction programs like SIFT, Polyphen2, Mutation Taster2, CADD etc. predicted this variant as likely disease causing. As per ACMG guidelines the variant has been classified as likely pathogenic. (less)
Age: 0-9 years
Sex: male
Geographic origin: India
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Pathogenic
(Dec 18, 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: SCV002819641.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: CTNS c.422C>T (p.Ser141Phe) 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.422C>T (p.Ser141Phe) 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-06 in 251494 control chromosomes. c.422C>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Cystinosis (example, Kalatzis_2004, Aldahmesh_2009, Owen_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <2% of normal cystine transport activity (Kalatzis_2004). Three 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
(Jan 20, 2022)
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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: SCV002064219.2
First in ClinVar: Jan 29, 2022 Last updated: Mar 04, 2023 |
Comment:
Published in vitro functional studies demonstrate a damaging effect due to the loss of cystine transport activity compared to wildtype (Kalatzis et al., 2004); In … (more)
Published in vitro functional studies demonstrate a damaging effect due to the loss of cystine transport activity compared to wildtype (Kalatzis et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19852576, 27885487, 15128704, 25326109, 29467429) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Nephropathic cystinosis
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048379.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.422C>T (p.Ser141Phe) in CTNS gene has been observed to be homozygous or in combination with another CTNS variant in individuals affected with … (more)
The missense variant c.422C>T (p.Ser141Phe) in CTNS gene has been observed to be homozygous or in combination with another CTNS variant in individuals affected with cystinosis, and has been shown to segregate with disease in a family (Kalatzis et al., 2004; Aldahmesh et al., 2009; Owen et al., 2015). Experimental studies have shown that this missense change abolishes cystine transport activity (Kalatzis et al., 2004; Deshpande et al., 2018). The missense variant c.422C>T (p.Ser141Phe) IN CTNS gene has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The p.Ser141Phe variant is reported with the allele frequency (0.0003%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Ser at position 141 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ser141Phe in CTNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Vomiting (present) , Abnormal blood ion concentration (present) , Renal tubular acidosis (present)
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Pathogenic
(Aug 04, 2022)
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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: SCV004215226.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 02, 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: SCV000947372.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 141 of the CTNS protein (p.Ser141Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 141 of the CTNS protein (p.Ser141Phe). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with cystinosis (PMID: 15128704, 19852576, 25326109). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 651886). 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, 29467429). For these reasons, this variant has been classified as Pathogenic. (less)
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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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A Genetic Screen for Investigating the Human Lysosomal CystineTransporter, Cystinosin. | Deshpande AA | Scientific reports | 2018 | PMID: 29467429 |
Common mutation causes cystinosis in the majority of black South African patients. | Owen EP | Pediatric nephrology (Berlin, Germany) | 2015 | PMID: 25326109 |
Characterization of CTNS mutations in Arab patients with cystinosis. | Aldahmesh MA | Ophthalmic genetics | 2009 | PMID: 19852576 |
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 |
Text-mined citations for rs1436441738 ...
HelpRecord last updated Apr 15, 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.