VCV000252749.18 - ClinVar

NM_030653.4(DDX11):c.1763-1G>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.

(9)

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_030653.4(DDX11):c.1763-1G>C

Variation ID: 252749 Accession: VCV000252749.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p11.21 12: 31097884 (GRCh38) [ NCBI UCSC ] 12: 31250818 (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 1, 2016	Oct 26, 2024	Oct 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_030653.4:c.1763-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001257144.2:c.1763-1G>C		splice acceptor
NM_001257145.2:c.1685-1G>C		splice acceptor
NM_001413692.1:c.1763-1G>C		splice acceptor
NM_001413693.1:c.1763-1G>C		splice acceptor
NM_001413694.1:c.1763-1G>C		splice acceptor
NM_001413695.1:c.1763-1G>C		splice acceptor
NM_001413696.1:c.1763-1G>C		splice acceptor
NM_001413697.1:c.1685-1G>C		splice acceptor
NM_001413698.1:c.1685-1G>C		splice acceptor
NM_001413699.1:c.1685-1G>C		splice acceptor
NM_001413700.1:c.1676-1G>C		splice acceptor
NM_001413702.1:c.1235-1G>C		splice acceptor
NM_001413703.1:c.1235-1G>C		splice acceptor
NM_001413704.1:c.902-1G>C		splice acceptor
NM_001413705.1:c.902-1G>C		splice acceptor
NM_001413706.1:c.797-1G>C		splice acceptor
NM_004399.3:c.1763-1G>C		splice acceptor
NM_152438.2:c.1763-1G>C		splice acceptor
NC_000012.12:g.31097884G>C
NC_000012.11:g.31250818G>C
NG_023352.1:g.29040G>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000012.12:31097883: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00022

The Genome Aggregation Database (gnomAD) 0.00024

Exome Aggregation Consortium (ExAC) 0.00027

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

The Genome Aggregation Database (gnomAD), exomes 0.00041

Links

ClinGen: CA6501496 dbSNP: rs148856317 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.
DDX11		-	-	GRCh38 GRCh37	218	247

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.
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 15, 2024	RCV000238763.11
Warsaw breakage syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 20, 2023	RCV000991173.6
DDX11-related condition	Pathogenic (1)	no assertion criteria provided	Jun 5, 2024	RCV004758676.1

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 (Oct 11, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Not provided Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000297327.3 First in ClinVar: Aug 01, 2016 Last updated: Dec 24, 2022
Pathogenic (Oct 15, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001767875.3 First in ClinVar: Aug 07, 2021 Last updated: Oct 26, 2024	Comment: mRNA studies demonstrate evidence of alternative splicing with the use of a cryptic splice acceptor site resulting in a frameshift in exon 18 (PMID: 31287223); … (more) mRNA studies demonstrate evidence of alternative splicing with the use of a cryptic splice acceptor site resulting in a frameshift in exon 18 (PMID: 31287223); 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: 33249554, 26689913, 30577886, 31824187, 34426522, 31287223, 36978159, 32855419, 33591602, 35032046) (less)
Pathogenic (Feb 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Warsaw breakage syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002807038.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Warsaw breakage syndrome Affected status: yes Allele origin: paternal	Duke University Health System Sequencing Clinic, Duke University Health System Accession: SCV003918986.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002228717.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 31287223‚ 32855419 Comment: This sequence change affects an acceptor splice site in intron 17 of the DDX11 gene. RNA analysis indicates that disruption of this splice site induces … (more) This sequence change affects an acceptor splice site in intron 17 of the DDX11 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs148856317, gnomAD 0.9%). Disruption of this splice site has been observed in individual(s) with Warsaw breakage syndrome (PMID: 31287223, 32855419). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 31287223). ClinVar contains an entry for this variant (Variation ID: 252749). Studies have shown that disruption of this splice site results in skipping of the first 4 nucleotides of exon 18 and introduces a premature termination codon (PMID: 31287223). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Warsaw breakage syndrome Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142431.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Comment: NG_023352.1(NM_030653.3):c.1763-1G>C in the DDX11 gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database.This variant is predicted to cause abnormal … (more) NG_023352.1(NM_030653.3):c.1763-1G>C in the DDX11 gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database.This variant is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM2. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928530.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971173.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Jun 05, 2024)	no assertion criteria provided Method: clinical testing	DDX11-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005351372.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The DDX11 c.1763-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the homozygous … (more) The DDX11 c.1763-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the homozygous state in individuals with Warsaw breakage syndrome (Rabin et al. 2019. PubMed ID: 31287223; Baker et al. 2019. PubMed ID: 30577886). RNA studies showed aberrant splicing (Rabin et al. 2019. PubMed ID: 31287223). In the gnomAD population database this variant is reported in 0.83% of alleles in individuals of Ashkenazi Jewish descent. Variants that disrupt the consensus splice acceptor site in DDX11 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

mRNA studies demonstrate evidence of alternative splicing with the use of a cryptic splice acceptor site resulting in a frameshift in exon 18 (PMID: 31287223); 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: 33249554, 26689913, 30577886, 31824187, 34426522, 31287223, 36978159, 32855419, 33591602, 35032046)

Comment:

This sequence change affects an acceptor splice site in intron 17 of the DDX11 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs148856317, gnomAD 0.9%). Disruption of this splice site has been observed in individual(s) with Warsaw breakage syndrome (PMID: 31287223, 32855419). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 31287223). ClinVar contains an entry for this variant (Variation ID: 252749). Studies have shown that disruption of this splice site results in skipping of the first 4 nucleotides of exon 18 and introduces a premature termination codon (PMID: 31287223). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

NG_023352.1(NM_030653.3):c.1763-1G>C in the DDX11 gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database.This variant is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM2.

Comment:

The DDX11 c.1763-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the homozygous state in individuals with Warsaw breakage syndrome (Rabin et al. 2019. PubMed ID: 31287223; Baker et al. 2019. PubMed ID: 30577886). RNA studies showed aberrant splicing (Rabin et al. 2019. PubMed ID: 31287223). In the gnomAD population database this variant is reported in 0.83% of alleles in individuals of Ashkenazi Jewish descent. Variants that disrupt the consensus splice acceptor site in DDX11 are expected to be pathogenic. This variant is interpreted 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
Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion.	van Schie JJM	Nature communications	2020	PMID: 32855419
Study of carrier frequency of Warsaw breakage syndrome in the Ashkenazi Jewish population and presentation of two cases.	Rabin R	American journal of medical genetics. Part A	2019	PMID: 31287223

Text-mined citations for rs148856317 ...

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 27, 2024

ClinVar Genomic variation as it relates to human health

NM_030653.4(DDX11):c.1763-1G>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148856317 ...