The c.3460C>T variant is present in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP at low frequency (MAF<0.003), including 3 homozygotes in gnomAD. The variant is also present in our in-house exome database at low frequency (MAF~004), in heterozygous state. The variant was reported earlier to ClinVar database (Accession: VCV000418766.3) with conflicting interpretations of pathogenicity (benign/uncertain significance), however clinical condition was not provided. In-silico pathogenicity prediction programs like PolyPhen-3, MutationTaster2, CADD etc. predicted this variant to be likely deleterious. However there are no documented functional studies to prove this. Due to lack of evidence the variant has been classified as un certain significance. The patient harbors another heterozygous missense variant of uncertain significance (c.3002T>C) in DOCK8 gene.

Variant summary: DOCK8 c.3460C>T (p.Arg1154Cys) results in a non-conservative amino acid change in the encoded protein sequence. 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. The variant allele was found at a frequency of 0.0029 in 251248 control chromosomes, predominantly at a frequency of 0.0068 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for disease-causing variants in DOCK8. c.3460C>T has been observed in a study in an US cohort of patients with common variable immunodeficiency without evidence for causality (von Beck_2024). These report(s) do 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 have been ascertained in the context of this evaluation (PMID: 39415980). ClinVar contains an entry for this variant (Variation ID: 418766). Based on the evidence outlined above, the variant was classified as likely benign.

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

DOCK8: BS2

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).