NM_203447.4(DOCK8):c.2482G>A (p.Ala828Thr) AND Combined immunodeficiency due to DOCK8 deficiency

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 29, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000793045.9

Allele description [Variation Report for NM_203447.4(DOCK8):c.2482G>A (p.Ala828Thr)]

NM_203447.4(DOCK8):c.2482G>A (p.Ala828Thr)

Gene:

DOCK8:dedicator of cytokinesis 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p24.3

Genomic location:

Preferred name:

NM_203447.4(DOCK8):c.2482G>A (p.Ala828Thr)

HGVS:

NC_000009.12:g.379812G>A
NG_017007.1:g.169948G>A
NM_001190458.2:c.2278G>A
NM_001193536.2:c.2278G>A
NM_203447.4:c.2482G>AMANE SELECT
NP_001177387.1:p.Ala760Thr
NP_001180465.1:p.Ala760Thr
NP_982272.2:p.Ala828Thr
NP_982272.2:p.Ala828Thr
LRG_196t1:c.2482G>A
LRG_196:g.169948G>A
LRG_196p1:p.Ala828Thr
NC_000009.11:g.379812G>A
NM_203447.3:c.2482G>A

Protein change:

A760T

Links:

dbSNP: rs138519226

NCBI 1000 Genomes Browser:

rs138519226

Molecular consequence:

NM_001190458.2:c.2278G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001193536.2:c.2278G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_203447.4:c.2482G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Combined immunodeficiency due to DOCK8 deficiency (HIES2)
Synonyms:: Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive; HIES autosomal recessive; Hyper-IgE recurrent infection syndrome, autosomal recessive; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009478; MedGen: C4722305; Orphanet: 217390; OMIM: 243700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000932380	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 29, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000932380

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 29, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000932380.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 828 of the DOCK8 protein (p.Ala828Thr). This variant is present in population databases (rs138519226, gnomAD 0.02%). 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: 640093). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 21, 2023

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