Submissions for variant NM_203447.4(DOCK8):c.295G>A (p.Glu99Lys)

dbSNP: rs547012088

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003596589	SCV000947615	uncertain significance	Autosomal recessive hyper-IgE syndrome	2022-02-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 99 of the DOCK8 protein (p.Glu99Lys). This variant is present in population databases (rs547012088, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with DOCK8-related conditions. ClinVar contains an entry for this variant (Variation ID: 652068). 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: "Probably 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323727	SCV004029980	uncertain significance	not specified	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: DOCK8 c.295G>A (p.Glu99Lys) results in a conservative amino acid change located in the N-terminal domain (IPR021816) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251366 control chromosomes, exclusively at a frequency of 0.0017 within the South Asian subpopulation in the gnomAD database (i.e., 53 heterozygotes and 0 homozygotes). The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in DOCK8 causing Severe Combined Immunodeficiency phenotype (0.00035), suggesting that the variant may be a benign polymorphism found primarily in populations of South Asian origin. However, c.295G>A has been reported in the literature in 2 homozygous siblings affected with autosomal recessive intellectual disability, and the variant was shown to segregate with disease (e.g., Riazuddin_2017). This report does not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 27457812). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.