ClinVar Miner

Submissions for variant NM_020812.4(DOCK6):c.5939+2T>C

gnomAD frequency: 0.00019  dbSNP: rs201387914
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001242778 SCV001415887 pathogenic not provided 2023-10-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 46 of the DOCK6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DOCK6 are known to be pathogenic (PMID: 21820096, 25824905). This variant is present in population databases (rs201387914, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with Aicardi-GoutieÃÄres syndrome and Adams-Oliver syndrome (PMID: 25824905, 28884918, 30111349). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253047). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001242778 SCV001817220 pathogenic not provided 2022-02-16 criteria provided, single submitter clinical testing 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: 25824905, 30111349, 31654484, 29961505, 29924900, 31589614, 28884918)
Revvity Omics, Revvity RCV000239583 SCV002021733 pathogenic Adams-Oliver syndrome 2 2020-04-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV002518540 SCV003621663 pathogenic Inborn genetic diseases 2021-06-02 criteria provided, single submitter clinical testing The c.5939+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 46 of the DOCK6 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the DOCK6 c.5939+2T>C alteration was observed in 0.02% (58/277380) of total alleles studied, with a frequency of 0.04% (46/127132) in the European (non-Finnish) subpopulation. This alteration has been reported in the literature in combination with other DOCK6 mutations in patients with features consistent with Adams-Oliver syndrome (Jones, 2017; Dugan, 2018). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
OMIM RCV000239583 SCV000297836 pathogenic Adams-Oliver syndrome 2 2016-08-11 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001242778 SCV001978647 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001242778 SCV001980096 likely pathogenic not provided no assertion criteria provided clinical testing

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