ClinVar Miner

Submissions for variant NM_203447.4(DOCK8):c.4346C>T (p.Ser1449Leu)

gnomAD frequency: 0.00006  dbSNP: rs370123223
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001704338 SCV000528262 likely benign not provided 2018-04-09 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27890707, 32888943)
Invitae RCV000691493 SCV000819276 uncertain significance Combined immunodeficiency due to DOCK8 deficiency 2022-10-05 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1449 of the DOCK8 protein (p.Ser1449Leu). This variant is present in population databases (rs370123223, gnomAD 0.02%). This missense change has been observed in individual(s) with DOCK8 deficiency (PMID: 27890707). ClinVar contains an entry for this variant (Variation ID: 386550). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DOCK8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics RCV000691493 SCV001524227 uncertain significance Combined immunodeficiency due to DOCK8 deficiency 2020-06-03 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity RCV000691493 SCV003830561 uncertain significance Combined immunodeficiency due to DOCK8 deficiency 2022-11-29 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003392247 SCV004110949 uncertain significance DOCK8-related disorder 2023-04-28 criteria provided, single submitter clinical testing The DOCK8 c.4346C>T variant is predicted to result in the amino acid substitution p.Ser1449Leu. This variant has been reported in the homozygous state in three related Saudi patients from a highly consanguineous family (Al Shekaili et al. 2017. PubMed ID: 27890707). Of note, these individuals were also homozygous for a splicing variant, c.4626+5G>A, in DOCK8 that was predicted to impact splicing based on splicing predication programs and abolish protein product via western blot analysis (Alamut Visual Plus v1.6.1; Al Shekaili et al. 2017. PubMed ID: 27890707). This variant was also reported in the compound heterozygous state in an individual with suspected primary immunodeficiency (Table E2 - Platt et al. 2021. PubMed ID: 32888943). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-428369-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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