VCV000526030.14 - ClinVar

NM_004937.3(CTNS):c.971-12G>A

Germline

Classification

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.

(6)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004937.3(CTNS):c.971-12G>A

Variation ID: 526030 Accession: VCV000526030.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.2 17: 3563518 (GRCh37) [ NCBI UCSC ] 17: 3660224 (GRCh38) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jun 17, 2024	Feb 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004937.3:c.971-12G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001031681.3:c.971-12G>A		intron variant
NM_001374492.1:c.971-12G>A		intron variant
NM_001374493.1:c.530-12G>A		intron variant
NM_001374494.1:c.530-12G>A		intron variant
NM_001374495.1:c.530-12G>A		intron variant
NM_001374496.1:c.530-12G>A		intron variant
NC_000017.11:g.3660224G>A
NC_000017.10:g.3563518G>A
NG_012489.2:g.28757G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:3660223:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA8291997 dbSNP: rs375952052 VarSome

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
Gene	OMIM	HI score Help 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.
CTNS		-	-	GRCh38 GRCh37	517	931

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.
Nephropathic cystinosis	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 23, 2024	RCV000664494.11
Infantile nephropathic cystinosis	Pathogenic (1)	criteria provided, single submitter	Mar 7, 2022	RCV001843534.10
Cystinosis	Pathogenic (1)	no assertion criteria provided	Feb 19, 2020	RCV001829749.9
Inborn genetic diseases Juvenile nephropathic cystinosis Ocular cystinosis	Pathogenic (1)	criteria provided, single submitter	Dec 16, 2023	RCV002528837.10

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.
Pathogenic (Feb 01, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Nephropathic cystinosis Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000788462.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 25326109
Pathogenic (Aug 30, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephropathic cystinosis Affected status: yes Allele origin: germline	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota Accession: SCV000889960.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (5) PubMed: 10556299‚ 12442267‚ 25326109‚ 9537412‚ 22450360 Number of individuals with the variant: 1
Pathogenic (Mar 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile nephropathic cystinosis Affected status: yes Allele origin: germline	Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi Accession: SCV002102787.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 Comment: splice site variant at Intron 11-exon 12 junction	Publications: PubMed (1) PubMed: 35738466 Number of individuals with the variant: 3 Age: 1-45 years Sex: mixed Geographic origin: India
Pathogenic (Dec 16, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000751432.7 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 28492532‚ 10556299‚ 22450360‚ 25326109‚ 12442267 Comment: This sequence change falls in intron 11 of the CTNS gene. It does not directly change the encoded amino acid sequence of the CTNS protein. … (more) This sequence change falls in intron 11 of the CTNS gene. It does not directly change the encoded amino acid sequence of the CTNS protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs375952052, gnomAD 0.006%). This variant has been observed in individual(s) with cystinosis (PMID: 10556299, 22450360, 25326109). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1310-12G>A. ClinVar contains an entry for this variant (Variation ID: 526030). Studies have shown that this variant results in the inclusion of the last 10 bp of intron 11 and introduces a new termination codon (PMID: 12442267). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephropathic cystinosis Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004212967.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Feb 19, 2020)	no assertion criteria provided Method: clinical testing	Cystinosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002093240.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

This sequence change falls in intron 11 of the CTNS gene. It does not directly change the encoded amino acid sequence of the CTNS protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs375952052, gnomAD 0.006%). This variant has been observed in individual(s) with cystinosis (PMID: 10556299, 22450360, 25326109). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1310-12G>A. ClinVar contains an entry for this variant (Variation ID: 526030). Studies have shown that this variant results in the inclusion of the last 10 bp of intron 11 and introduces a new termination codon (PMID: 12442267). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic and clinical profile of patients with hypophosphatemic rickets.	Marik B	European journal of medical genetics	2022	PMID: 35738466
Common mutation causes cystinosis in the majority of black South African patients.	Owen EP	Pediatric nephrology (Berlin, Germany)	2015	PMID: 25326109
Two novel CTNS mutations in cystinosis patients in Thailand.	Yeetong P	Gene	2012	PMID: 22450360
Identification of 14 novel CTNS mutations and characterization of seven splice site mutations associated with cystinosis.	Kalatzis V	Human mutation	2002	PMID: 12442267
Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin.	Attard M	Human molecular genetics	1999	PMID: 10556299
A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis.	Town M	Nature genetics	1998	PMID: 9537412

Text-mined citations for rs375952052 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_004937.3(CTNS):c.971-12G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs375952052 ...