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

gnomAD frequency: 0.00024  dbSNP: rs148856317

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238763	SCV000297327	pathogenic	not provided	2015-10-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000238763	SCV001767875	pathogenic	not provided	2023-03-09	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000238763	SCV002228717	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000991173	SCV002807038	pathogenic	Warsaw breakage syndrome	2022-02-14	criteria provided, single submitter	clinical testing
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000991173	SCV003918986	pathogenic	Warsaw breakage syndrome	2023-04-20	criteria provided, single submitter	research
Reproductive Health Research and Development, BGI Genomics	RCV000991173	SCV001142431	likely pathogenic	Warsaw breakage syndrome	2020-01-06	no assertion criteria provided	curation	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000238763	SCV001928530	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000238763	SCV001971173	likely pathogenic	not provided		no assertion criteria provided	clinical testing