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

gnomAD frequency: 0.00019  dbSNP: rs201387914

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242778	SCV001415887	pathogenic	not provided	2025-01-13	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	2024-11-29	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; however, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin, 2019). Based on data from gnomAD, the C allele has an overall frequency of 0.021% (58/277380) total alleles studied. The highest observed frequency was 0.036% (46/127132) of European (non-Finnish) alleles. This alteration has been reported in the literature in combination with other DOCK6 variants 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	2023-11-02	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
PreventionGenetics, part of Exact Sciences	RCV004751400	SCV005351052	pathogenic	DOCK6-related disorder	2024-06-19	no assertion criteria provided	clinical testing	The DOCK6 c.5939+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with Adams-Oliver syndrome, with the phenotype co-segregating in one family (see for example - Sukalo. 2015. PubMed ID: 25824905; Jones et al. 2017. PubMed ID: 28884918; Dudoignon et al. 2020. PubMed ID: 31654484). This variant has also been documented in the compound heterozygous state in an individual who fulfilled the clinical criteria for Aicardi-Goutieres syndrome (Tonduti et al. 2018. PubMed ID: 30111349). This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in DOCK6 are expected to be pathogenic. This variant is interpreted as pathogenic.