ClinVar Miner

Submissions for variant NM_203447.3(DOCK8):c.494C>T (p.Ser165Leu) (rs146490788)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000379147 SCV000479547 uncertain significance Hyper-IgE syndrome 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000762542 SCV000576542 uncertain significance not provided 2017-04-28 criteria provided, single submitter clinical testing The S165L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is observed in 60/66688 (0.09%) alleles from individuals of European background in the ExAC dataset, including one homozygote (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, S165L 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. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000762542 SCV000892872 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768199 SCV000898650 uncertain significance Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive 2017-10-10 criteria provided, single submitter clinical testing DOCK8 NM_203447.3 exon 5 p.Ser165Leu (c.494C>T): This variant has not been reported in the literature but is present in 0.2% (28/10150) of Ashkenazi Jewish alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs146490788). This variant is present in ClinVar (Variation ID:366541). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Invitae RCV000768199 SCV000932479 uncertain significance Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 165 of the DOCK8 protein (p.Ser165Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs146490788, ExAC 0.09%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals with DOCK8-related disease. ClinVar contains an entry for this variant (Variation ID: 366541). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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