Submissions for variant NM_203447.4(DOCK8):c.3460C>T (p.Arg1154Cys)

gnomAD frequency: 0.00170  dbSNP: rs34390308

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479850	SCV000566074	likely benign	not provided	2019-03-28	criteria provided, single submitter	clinical testing
Invitae	RCV003762746	SCV000766908	benign	Autosomal recessive hyper-IgE syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	RCV001086901	SCV001244221	uncertain significance	Combined immunodeficiency due to DOCK8 deficiency	2020-04-17	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001086901	SCV001331911	likely benign	Combined immunodeficiency due to DOCK8 deficiency	2018-01-13	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 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.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001086901	SCV001984706	benign	Combined immunodeficiency due to DOCK8 deficiency	2020-12-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821389	SCV002072307	likely benign	not specified	2021-11-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000479850	SCV004161715	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	DOCK8: BS2
PreventionGenetics, part of Exact Sciences	RCV003925401	SCV004741561	likely benign	DOCK8-related disorder	2020-03-02	criteria provided, single submitter	clinical testing	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).