ClinVar Miner

Submissions for variant NM_203447.4(DOCK8):c.4019A>G (p.Tyr1340Cys)

gnomAD frequency: 0.00276  dbSNP: rs116920018
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414337 SCV000490516 uncertain significance not specified 2016-12-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DOCK8 gene. The Y1272C variant has not been published as a germline pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project and the 1000 Genomes Project Consortium report Y1272C was observed in 31/8600 (0.36%) alleles and 3/694 (0.43%) from individuals of European and mixed American ancestry, respectively, indicating it may be a rare variant in these populations. Additionally, the variant has been observed in the homozygous state in two unaffected individuals at GeneDx. However, the Y1272C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000414337 SCV000711311 likely benign not specified 2016-05-20 criteria provided, single submitter clinical testing p.Tyr1340Cys in exon 31 of DOCK8: This variant is not expected to have clinical significance because it has been identified in 0.7% (48/6614) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC,; dbSNP rs116920018).
Invitae RCV003761965 SCV000766922 benign Autosomal recessive hyper-IgE syndrome 2024-01-24 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000645180 SCV000898652 uncertain significance Combined immunodeficiency due to DOCK8 deficiency 2021-03-30 criteria provided, single submitter clinical testing DOCK8 NM_203447.3 exon 31 p.Tyr1340Cys (c.4019A>G):This variant has not been reported in the literature but is present in 0.6% (175/25788) of European (Finnish) alleles, including 1 homozygote in the Genome Aggregation Database ( This variant is present in ClinVar (Variation ID:372357). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, Illumina RCV000645180 SCV001331214 benign Combined immunodeficiency due to DOCK8 deficiency 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV001507743 SCV001713478 uncertain significance not provided 2022-09-30 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000414337 SCV002072309 uncertain significance not specified 2021-08-30 criteria provided, single submitter clinical testing DNA sequence analysis of the DOCK8 gene demonstrated a sequence change, c.4019A>G, in exon 31 that results in an amino acid change, p.Tyr1340Cys. This sequence change has been described in the gnomAD database with a frequency of 0.65% in the non-Finnish European subpopulation and includes 2 homozygous individuals (dbSNP rs116920018). The p.Tyr1340Cys change affects a highly conserved amino acid residue located in a domain of the DOCK8 protein that is not known to be functional. The p.Tyr1340Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with DOCK8-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Tyr1340Cys change remains unknown at this time.
CeGaT Center for Human Genetics Tuebingen RCV001507743 SCV004161721 likely benign not provided 2023-10-01 criteria provided, single submitter clinical testing DOCK8: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000414337 SCV004241186 likely benign not specified 2023-12-15 criteria provided, single submitter clinical testing Variant summary: DOCK8 c.4019A>G (p.Tyr1340Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 1614156 control chromosomes in the gnomAD database, including 21 homozygotes, strongly suggesting the variant is a benign polymorphism. c.4019A>G has been reported in the literature in the heterozygous state in an individual with some clinical features of Combined Immunodeficiency Due To DOCK8 Deficiency, without strong evidence for causality (Similuk_2022). This report does not provide unequivocal conclusions about association of the variant with Combined Immunodeficiency Due To DOCK8 Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35753512). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as benign/likely benign and four classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences RCV003922668 SCV004741980 likely benign DOCK8-related disorder 2020-05-22 criteria provided, single submitter 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).

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