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NM_203447.4(DOCK8):c.4346C>T (p.Ser1449Leu) AND Combined immunodeficiency due to DOCK8 deficiency

Germline classification:
Uncertain significance (3 submissions)
Last evaluated:
Nov 29, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000691493.11

Allele description [Variation Report for NM_203447.4(DOCK8):c.4346C>T (p.Ser1449Leu)]

NM_203447.4(DOCK8):c.4346C>T (p.Ser1449Leu)

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.4346C>T (p.Ser1449Leu)
HGVS:
  • NC_000009.12:g.428369C>T
  • NG_017007.1:g.218505C>T
  • NM_001190458.2:c.4046C>T
  • NM_001193536.2:c.4142C>T
  • NM_203447.4:c.4346C>TMANE SELECT
  • NP_001177387.1:p.Ser1349Leu
  • NP_001180465.1:p.Ser1381Leu
  • NP_982272.2:p.Ser1449Leu
  • NP_982272.2:p.Ser1449Leu
  • LRG_196t1:c.4346C>T
  • LRG_196:g.218505C>T
  • LRG_196p1:p.Ser1449Leu
  • NC_000009.11:g.428369C>T
  • NM_203447.3:c.4346C>T
Protein change:
S1349L
Links:
dbSNP: rs370123223
NCBI 1000 Genomes Browser:
rs370123223
Molecular consequence:
  • NM_001190458.2:c.4046C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001193536.2:c.4142C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_203447.4:c.4346C>T - 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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000819276Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Oct 5, 2022)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001524227Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jun 3, 2020)
unknownclinical testing

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

SCV003830561Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Nov 29, 2022)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Novel mutation in DOCK8-HIES with severe phenotype and successful transplantation.

Al Shekaili L, Sheikh F, Al Gazlan S, Al Dhekri H, Al Mousa H, Al Ghonaium A, Al Saud B, Al Mohsen S, Rehan Khaliq AM, Al Sumayli S, Al Zahrani M, Dababo A, AlKawi A, Hawwari A, Arnaout R.

Clin Immunol. 2017 May;178:39-44. doi: 10.1016/j.clim.2016.08.002. Epub 2016 Nov 23.

PubMed [citation]
PMID:
27890707

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000819276.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1449 of the DOCK8 protein (p.Ser1449Leu). This variant is present in population databases (rs370123223, gnomAD 0.02%). This missense change has been observed in individual(s) with DOCK8 deficiency (PMID: 27890707). ClinVar contains an entry for this variant (Variation ID: 386550). 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 not expected to disrupt DOCK8 protein function. 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.

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

From Baylor Genetics, SCV001524227.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Revvity Omics, Revvity, SCV003830561.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 29, 2024