Submissions for variant NM_203447.4(DOCK8):c.3312G>C (p.Glu1104Asp)

gnomAD frequency: 0.00054  dbSNP: rs138810908

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000526922	SCV000480270	uncertain significance	Combined immunodeficiency due to DOCK8 deficiency	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV003761959	SCV000645698	uncertain significance	Autosomal recessive hyper-IgE syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1104 of the DOCK8 protein (p.Glu1104Asp). This variant is present in population databases (rs138810908, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 366974). 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 expected to disrupt DOCK8 protein function with a positive predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000526922	SCV000897523	uncertain significance	Combined immunodeficiency due to DOCK8 deficiency	2018-10-31	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000526922	SCV002099190	uncertain significance	Combined immunodeficiency due to DOCK8 deficiency	2021-06-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987525	SCV004804491	likely benign	not specified	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: DOCK8 c.3312G>C (p.Glu1104Asp) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 251296 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in DOCK8 causing Severe Combined Immunodeficiency phenotype (0.00035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3312G>C has been reported in the literature in individuals affected with Common Variable Immunodeficiency and Autism/Developmental Delay, without strong evidence for causality (Maffucci_2016, Guo_2018). These report(s) do 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 publications have been ascertained in the context of this evaluation (PMID: 30564305, 27379089). ClinVar contains an entry for this variant (Variation ID: 366974, VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723965	SCV001951929	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723965	SCV001966086	uncertain significance	not provided		no assertion criteria provided	clinical testing