Submissions for variant NM_203447.4(DOCK8):c.380G>A (p.Arg127His)

gnomAD frequency: 0.00196  dbSNP: rs150742426

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000645163	SCV000479543	likely benign	Combined immunodeficiency due to DOCK8 deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV001531727	SCV000730738	likely benign	not provided	2018-12-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32084423)
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090612	SCV000766905	benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000645163	SCV001468372	uncertain significance	Combined immunodeficiency due to DOCK8 deficiency	2021-03-30	criteria provided, single submitter	clinical testing	DOCK8 NM_203447.3 exon 4 p.Arg127His (c.380G>A): This variant has been reported in the literature as a compound heterozygote in 1 individual with inflammatory bowel disease (IBD) (Crowley 2020 PMID:32084423). This variant is present in 0.3% (464/129078) of European alleles, including 2 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-289557-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as Benign or Likely Benign (Variation ID:366538). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV001531727	SCV001746985	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	DOCK8: BP4, BS2
Genetic Services Laboratory, University of Chicago	RCV001821120	SCV002066416	likely benign	not specified	2021-11-30	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251744	SCV001427485	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001531727	SCV001931598	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001531727	SCV001963278	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001531727	SCV001971881	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003922651	SCV004748786	likely benign	DOCK8-related disorder	2020-06-03	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).