VCV000140454.18 - ClinVar

NM_001905.4(CTPS1):c.1692-1G>C

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.

(8)

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_001905.4(CTPS1):c.1692-1G>C

Variation ID: 140454 Accession: VCV000140454.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.2 1: 41010160 (GRCh38) [ NCBI UCSC ] 1: 41475832 (GRCh37) [ 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 22, 2016	Sep 29, 2024	Sep 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001905.4:c.1692-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001301237.2:c.1224-1G>C		splice acceptor
NC_000001.11:g.41010160G>C
NC_000001.10:g.41475832G>C
NG_034208.1:g.35862G>C
LRG_1229:g.35862G>C
LRG_1229t1:c.1692-1G>C

... more HGVS ... less HGVS

Protein change

Other names

IVS17, G-C, -1 (rs145092287)

Canonical SPDI

NC_000001.11:41010159:G:C

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) 0.00010

The Genome Aggregation Database (gnomAD), exomes 0.00010

The Genome Aggregation Database (gnomAD) 0.00015

Trans-Omics for Precision Medicine (TOPMed) 0.00019

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

Links

ClinGen: CA215010 OMIM: 123860.0001 dbSNP: rs145092287 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.
CTPS1		-	-	GRCh38 GRCh37	239	277

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.
Severe combined immunodeficiency due to CTPS1 deficiency	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 14, 2024	RCV000128633.17
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 10, 2024	RCV000413591.5

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 (Jul 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe combined immunodeficiency due to CTPS1 deficiency Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001522698.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Mar 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502201.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (3) PubMed: 24870241‚ 27638562‚ 32161190 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Jan 14, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Severe combined immunodeficiency due to CTPS1 deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000774175.8 First in ClinVar: Aug 22, 2016 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 28492532‚ 24870241‚ 27638562‚ 32161190‚ 17576681‚ 9536098 Comment: This sequence change affects an acceptor splice site in intron 17 of the CTPS1 gene. While this variant is not anticipated to result in nonsense … (more) This sequence change affects an acceptor splice site in intron 17 of the CTPS1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs145092287, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with combined immunodeficiency (PMID: 24870241, 27638562, 32161190). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140454). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24870241). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 10, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000490997.3 First in ClinVar: Jan 09, 2017 Last updated: Sep 29, 2024	Comment: Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more) Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24870241, 27638562, 34758253, 27543071, 31345272, 35983265, 32812031, 32161190) (less)
Pathogenic (Jun 12, 2014)	no assertion criteria provided Method: literature only	IMMUNODEFICIENCY 24 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000172268.2 First in ClinVar: Jul 20, 2014 Last updated: Aug 22, 2016	Publications: PubMed (1) PubMed: 24870241 Comment on evidence: In 8 children from 5 families from the northwest region of England who manifested a combined deficiency of adaptive immunity (IMD24; 615897), Martin et al. … (more) In 8 children from 5 families from the northwest region of England who manifested a combined deficiency of adaptive immunity (IMD24; 615897), Martin et al. (2014) detected a homozygous G-to-C transversion at the -1 position of intron 17 of the CTPS1 gene (rs145092287) using whole-exome and confirmatory Sanger sequencing. The authors referred to the mutation as IVS18-1G-C and noted its genomic location as position 41475832 on chromosome 1. The mutation resulted in expression of an abnormal transcript lacking exon 18. The mutation was considered deleterious since CTPS1 protein expression could not be detected in lysates of EBV-transformed B cells and T-cell blasts from patients. All parents and unaffected sibs tested were heterozygous carriers. Sequencing of a cohort of 752 healthy individuals from the northwest of England gave an estimated frequency of homozygosity of 1 in 560,000. This frequency represented a more than 10-fold increase compared to the frequency estimated from available exome databases. Whole-exome sequencing data and analysis of polymorphic microsatellite markers in all patients revealed a common region of homozygosity of 1.1 Mb surrounding the mutation. These data indicated a founder effect. (less)
Pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Severe combined immunodeficiency due to CTPS1 deficiency Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760030.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Pathogenic (Sep 16, 2022)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV003839409.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: DNA sequence analysis of the CTPS1 gene demonstrated a sequence change in the canonical splice acceptor site of intron 17, c.1692-1G>C. This sequence change is … (more) DNA sequence analysis of the CTPS1 gene demonstrated a sequence change in the canonical splice acceptor site of intron 17, c.1692-1G>C. This sequence change is predicted to affect normal splicing of the CTPS1 gene and result in an abnormal/unstable protein. This sequence change has been previously described in the homozygous state in multiple individuals with CTPS1-related combined immunodeficiency (PMIDs: 24870241, 27638562, 32161190) and is reported to be a founder mutation in the northwest England population. Experimental studies have shown that this sequence change is responsible for reduced protein expression and may result in unstable protein lacking the last exon (PMIDs: 24870241, 32161190). This sequence change has been described in the gnomAD database with a frequency of 0.018% in the European subpopulation (dbSNP rs145092287). These collective evidences indicate that this sequence change is pathogenic. (less)
Pathogenic (May 03, 2019)	no assertion criteria provided Method: clinical testing	Severe combined immunodeficiency due to CTPS1 deficiency Affected status: yes Allele origin: inherited	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust Accession: SCV000926210.1 First in ClinVar: Jul 15, 2019 Last updated: Jul 15, 2019

Comment:

This sequence change affects an acceptor splice site in intron 17 of the CTPS1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs145092287, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with combined immunodeficiency (PMID: 24870241, 27638562, 32161190). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140454). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24870241). For these reasons, this variant has been classified as Pathogenic.

Comment:

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24870241, 27638562, 34758253, 27543071, 31345272, 35983265, 32812031, 32161190)

Comment:

DNA sequence analysis of the CTPS1 gene demonstrated a sequence change in the canonical splice acceptor site of intron 17, c.1692-1G>C. This sequence change is predicted to affect normal splicing of the CTPS1 gene and result in an abnormal/unstable protein. This sequence change has been previously described in the homozygous state in multiple individuals with CTPS1-related combined immunodeficiency (PMIDs: 24870241, 27638562, 32161190) and is reported to be a founder mutation in the northwest England population. Experimental studies have shown that this sequence change is responsible for reduced protein expression and may result in unstable protein lacking the last exon (PMIDs: 24870241, 32161190). This sequence change has been described in the gnomAD database with a frequency of 0.018% in the European subpopulation (dbSNP rs145092287). These collective evidences indicate that this sequence change is 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
Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation.	Martin E	JCI insight	2020	PMID: 32161190
CTP Synthase 1 Deficiency in Successfully Transplanted Siblings with Combined Immune Deficiency and Chronic Active EBV Infection.	Kucuk ZY	Journal of clinical immunology	2016	PMID: 27638562
CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation.	Martin E	Nature	2014	PMID: 24870241
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
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs145092287 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001905.4(CTPS1):c.1692-1G>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145092287 ...