NM_030653.4(DDX11):c.1763-1G>C AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000238763.9

Allele description [Variation Report for NM_030653.4(DDX11):c.1763-1G>C]

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

Gene:

DDX11:DEAD/H-box helicase 11 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p11.21

Genomic location:

Preferred name:

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

HGVS:

NC_000012.12:g.31097884G>C
NG_023352.1:g.29040G>C
NM_001257144.2:c.1763-1G>C
NM_001257145.2:c.1685-1G>C
NM_001413692.1:c.1763-1G>C
NM_001413693.1:c.1763-1G>C
NM_001413694.1:c.1763-1G>C
NM_001413695.1:c.1763-1G>C
NM_001413696.1:c.1763-1G>C
NM_001413697.1:c.1685-1G>C
NM_001413698.1:c.1685-1G>C
NM_001413699.1:c.1685-1G>C
NM_001413700.1:c.1676-1G>C
NM_001413702.1:c.1235-1G>C
NM_001413703.1:c.1235-1G>C
NM_001413704.1:c.902-1G>C
NM_001413705.1:c.902-1G>C
NM_001413706.1:c.797-1G>C
NM_004399.3:c.1763-1G>C
NM_030653.4:c.1763-1G>CMANE SELECT
NM_152438.2:c.1763-1G>C
NC_000012.11:g.31250818G>C
NM_030653.3:c.1763-1G>C

Links:

dbSNP: rs148856317

NCBI 1000 Genomes Browser:

rs148856317

Molecular consequence:

NM_001257144.2:c.1763-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001257145.2:c.1685-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413692.1:c.1763-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413693.1:c.1763-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413694.1:c.1763-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413695.1:c.1763-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413696.1:c.1763-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413697.1:c.1685-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413698.1:c.1685-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413699.1:c.1685-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413700.1:c.1676-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413702.1:c.1235-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413703.1:c.1235-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413704.1:c.902-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413705.1:c.902-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001413706.1:c.797-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_004399.3:c.1763-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_030653.4:c.1763-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_152438.2:c.1763-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000297327	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Pathogenic (Oct 11, 2015)	unknown	clinical testing	DGD_Variant_Analysis_Guidelines.docx, Citation Link,
SCV001767875	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 9, 2023)	germline	clinical testing	Citation Link,
SCV001928530	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001971173	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV002228717	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32855419, 31287223, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion.

van Schie JJM, Faramarz A, Balk JA, Stewart GS, Cantelli E, Oostra AB, Rooimans MA, Parish JL, de Almeida Estéves C, Dumic K, Barisic I, Diderich KEM, van Slegtenhorst MA, Mahtab M, Pisani FM, Te Riele H, Ameziane N, Wolthuis RMF, de Lange J.

Nat Commun. 2020 Aug 27;11(1):4287. doi: 10.1038/s41467-020-18066-8.

PubMed [citation]

PMID:: 32855419
PMCID:: PMC7452896

Study of carrier frequency of Warsaw breakage syndrome in the Ashkenazi Jewish population and presentation of two cases.

Rabin R, Hirsch Y, Johansson MM, Ekstein J, Zeevi DA, Keena B, Zackai EH, Pappas J.

Am J Med Genet A. 2019 Oct;179(10):2144-2151. doi: 10.1002/ajmg.a.61284. Epub 2019 Jul 9.

PubMed [citation]

PMID:: 31287223

See all PubMed Citations (3)

Details of each submission

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000297327.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001767875.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

mRNA studies demonstrate evidence of alternative splicing with the use of a cryptic splice acceptor site resulting in a frameshift in exon 18 (Rabin et al., 2019); 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: 31287223, 26689913, 30577886, 31824187, 33591602, 34426522, 35032046)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001928530.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001971173.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002228717.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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