ClinVar Genomic variation as it relates to human health
NM_004937.3(CTNS):c.681G>A (p.Glu227=)
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.681G>A (p.Glu227=)
Variation ID: 553330 Accession: VCV000553330.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 3656795 (GRCh38) [ NCBI UCSC ] 17: 3560089 (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 5, 2018 Feb 28, 2024 Sep 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004937.3:c.681G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004928.2:p.Glu227= synonymous NM_001031681.3:c.681G>A NP_001026851.2:p.Glu227= synonymous NM_001374492.1:c.681G>A NP_001361421.1:p.Glu227= synonymous NM_001374493.1:c.240G>A NP_001361422.1:p.Glu80= synonymous NM_001374494.1:c.240G>A NP_001361423.1:p.Glu80= synonymous NM_001374495.1:c.240G>A NP_001361424.1:p.Glu80= synonymous NM_001374496.1:c.240G>A NP_001361425.1:p.Glu80= synonymous NC_000017.11:g.3656795G>A NC_000017.10:g.3560089G>A NG_012489.2:g.25328G>A - Protein change
- Other names
- p.Glu227=
- Canonical SPDI
- NC_000017.11:3656794:G:A
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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.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 25, 2023 | RCV000668750.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 17, 2021 | RCV001543503.9 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 19, 2021 | RCV001829850.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 7, 2021 | RCV002531208.9 |
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
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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
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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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Pathogenic
(Aug 15, 2017)
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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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Counsyl
Accession: SCV000793400.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Jun 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762115.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Aggressive behavior (present) , Specific learning disability (present) , Metabolic acidosis (present) , Hypokalemia (present) , Short stature (present) , Flat face (present)
Sex: male
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Nephropathic cystinosis
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841997.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide supporting evidence of the variant having a damaging effect on the gene … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 19852576). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.80). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23640116 / 19852576‚Äö21786142). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000553330). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Renal Fanconi syndrome (present)
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Pathogenic
(Sep 04, 2023)
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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:
inherited
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Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences
Accession: SCV004031449.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
Comment:
In-Silico PredictorsPP3: Pathogenic Strong
Age: 0-9 years
Sex: female
Ethnicity/Population group: Turkish
Geographic origin: West Azerbaijan(Iran)
Comment on evidence:
missense variant type:snv
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Pathogenic
(Sep 25, 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: SCV004212946.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 07, 2021)
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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: SCV001591757.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing … (more)
For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site, which introduces a premature termination codon (PMID: 19852576). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 553330). This variant has been observed in individuals with cystinosis (PMID: 19852576, 21786142). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 227 of the CTNS mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CTNS protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. (less)
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Pathogenic
(Oct 19, 2021)
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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: SCV002093232.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 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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The first molecular genetics analysis of individuals suffering from nephropatic cystinosis in the Southwestern Iran. | Shahkarami S | Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia | 2013 | PMID: 23640116 |
Genetic basis of cystinosis in Turkish patients: a single-center experience. | Topaloglu R | Pediatric nephrology (Berlin, Germany) | 2012 | PMID: 21786142 |
Characterization of CTNS mutations in Arab patients with cystinosis. | Aldahmesh MA | Ophthalmic genetics | 2009 | PMID: 19852576 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Identification of 14 novel CTNS mutations and characterization of seven splice site mutations associated with cystinosis. | Kalatzis V | Human mutation | 2002 | PMID: 12442267 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs778414542 ...
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.