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

gnomAD frequency: 0.00019  dbSNP: rs201387914

Total submissions: 7

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