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NM_203447.4(DOCK8):c.380G>A (p.Arg127His) AND Combined immunodeficiency due to DOCK8 deficiency

Germline classification:
Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:
Mar 30, 2021
Review status:
criteria provided, conflicting classifications
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:
RCV000645163.23

Allele description [Variation Report for NM_203447.4(DOCK8):c.380G>A (p.Arg127His)]

NM_203447.4(DOCK8):c.380G>A (p.Arg127His)

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.380G>A (p.Arg127His)
HGVS:
  • NC_000009.12:g.289557G>A
  • NG_017007.1:g.79693G>A
  • NM_001190458.2:c.176G>A
  • NM_001193536.2:c.176G>A
  • NM_203447.4:c.380G>AMANE SELECT
  • NP_001177387.1:p.Arg59His
  • NP_001180465.1:p.Arg59His
  • NP_982272.2:p.Arg127His
  • NP_982272.2:p.Arg127His
  • LRG_196t1:c.380G>A
  • LRG_196:g.79693G>A
  • LRG_196p1:p.Arg127His
  • NC_000009.11:g.289557G>A
  • NM_203447.3:c.380G>A
Protein change:
R127H
Links:
dbSNP: rs150742426
NCBI 1000 Genomes Browser:
rs150742426
Molecular consequence:
  • NM_001190458.2:c.176G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001193536.2:c.176G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_203447.4:c.380G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Combined immunodeficiency due to DOCK8 deficiency (HIES2)
Synonyms:
HIES autosomal recessive; Hyper-IgE recurrent infection syndrome, autosomal recessive; HYPER-IgE RECURRENT INFECTION SYNDROME 2, AUTOSOMAL RECESSIVE; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009478; MedGen: C4722305; Orphanet: 217390; OMIM: 243700

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000479543Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)		Likely benign
(Jan 13, 2018) 		germlineclinical testing

Citation Link,

SCV001468372Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 30, 2021) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000479543.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV001468372.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

DOCK8 NM_203447.3 exon 4 p.Arg127His (c.380G>A): This variant has been reported in the literature as a compound heterozygote in 1 individual with inflammatory bowel disease (IBD) (Crowley 2020 PMID:32084423). This variant is present in 0.3% (464/129078) of European alleles, including 2 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-289557-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as Benign or Likely Benign (Variation ID:366538). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 7, 2025