NM_006118.4(HAX1):c.256C>T (p.Arg86Ter) AND Kostmann syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 23, 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:: RCV000004917.10

Allele description [Variation Report for NM_006118.4(HAX1):c.256C>T (p.Arg86Ter)]

NM_006118.4(HAX1):c.256C>T (p.Arg86Ter)

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.256C>T (p.Arg86Ter)

HGVS:

NC_000001.11:g.154273538C>T
NG_007369.1:g.5976C>T
NM_001018837.2:c.112C>T
NM_006118.4:c.256C>TMANE SELECT
NP_001018238.1:p.Arg38Ter
NP_006109.2:p.Arg86Ter
NP_006109.2:p.Arg86Ter
LRG_64t1:c.256C>T
LRG_64:g.5976C>T
LRG_64p1:p.Arg86Ter
NC_000001.10:g.154246014C>T
NM_006118.3:c.256C>T

Protein change:

R38*; ARG86TER

Links:

OMIM: 605998.0005; dbSNP: rs121908165

NCBI 1000 Genomes Browser:

rs121908165

Molecular consequence:

NM_001018837.2:c.112C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_006118.4:c.256C>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
SCV000025093	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2008)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001202665	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 23, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18055975, 18330843, 18611981, 28102861, 17187068, 28492532
SCV001461737	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000025093

OMIM

no assertion criteria provided

Pathogenic
(Dec 1, 2008)

germline

literature only

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

SCV001202665

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 23, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001461737

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 16, 2020)

germline

clinical testing

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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency.

Matsubara K, Imai K, Okada S, Miki M, Ishikawa N, Tsumura M, Kato T, Ohara O, Nonoyama S, Kobayashi M.

Haematologica. 2007 Dec;92(12):e123-5.

PubMed [citation]

PMID:: 18055975

Association of HAX1 deficiency with neurological disorder.

Rezaei N, Chavoshzadeh Z, R Alaei O, Sandrock I, Klein C.

Neuropediatrics. 2007 Oct;38(5):261-3. doi: 10.1055/s-2008-1062704.

PubMed [citation]

PMID:: 18330843

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000025093.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 3 unrelated Japanese patients with autosomal recessive severe congenital neutropenia (SCN3; 610738), Ishikawa et al. (2008) identified a homozygous 256C-T transition in the HAX1 gene, resulting in an arg86-to-ter (R86X) substitution. Two additional Japanese patients, who were sibs, were compound heterozygous for R86X and a 59-bp deletion, resulting in a frameshift and premature termination (605998.0006). In addition to neutropenia, all patients had developmental delay, and the 3 homozygous patients also developed epilepsy. Both HAX1 isoforms were affected in all patients.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001202665.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4654). This premature translational stop signal has been observed in individual(s) with severe congenital neutropenia (PMID: 17187068, 18055975, 18330843, 18611981, 28102861). This variant is present in population databases (rs121908165, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg86*) 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).

#	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

From Natera, Inc., SCV001461737.1

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

#	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: Jan 13, 2025

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