NM_006118.4(HAX1):c.349G>T (p.Glu117Ter) AND Kostmann syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 16, 2024
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:: RCV001385664.5

Allele description [Variation Report for NM_006118.4(HAX1):c.349G>T (p.Glu117Ter)]

NM_006118.4(HAX1):c.349G>T (p.Glu117Ter)

Gene:

HAX1:HCLS1 associated protein X-1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q21.3

Genomic location:

Preferred name:

NM_006118.4(HAX1):c.349G>T (p.Glu117Ter)

HGVS:

NC_000001.11:g.154273806G>T
NG_007369.1:g.6244G>T
NM_001018837.2:c.205G>T
NM_006118.4:c.349G>TMANE SELECT
NP_001018238.1:p.Glu69Ter
NP_006109.2:p.Glu117Ter
LRG_64:g.6244G>T
NC_000001.10:g.154246282G>T

Protein change:

E117*

Links:

dbSNP: rs1487742962

NCBI 1000 Genomes Browser:

rs1487742962

Molecular consequence:

NM_001018837.2:c.205G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_006118.4:c.349G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Kostmann syndrome (SCN3)
Synonyms:: Kostmann disease; Agranulocytosis infantile; Autosomal recessive severe congenital neutropenia type 3
Identifiers:: MONDO: MONDO:0012548; MedGen: C5235141; Orphanet: 99749; OMIM: 610738

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001585606	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17187068, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001585606

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 16, 2024)

germline

clinical testing

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

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

HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease).

Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, Rathinam C, Boztug K, Schwinzer B, Rezaei N, Bohn G, Melin M, Carlsson G, Fadeel B, Dahl N, Palmblad J, Henter JI, Zeidler C, Grimbacher B, Welte K.

Nat Genet. 2007 Jan;39(1):86-92. Epub 2006 Dec 24.

PubMed [citation]

PMID:: 17187068

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001585606.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Glu117*) in the HAX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HAX1 are known to be pathogenic (PMID: 17187068). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with HAX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1072845). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 29, 2024

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