NM_006118.4(HAX1):c.428G>C (p.Gly143Ala) AND Kostmann syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 24, 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:: RCV000697014.9

Allele description [Variation Report for NM_006118.4(HAX1):c.428G>C (p.Gly143Ala)]

NM_006118.4(HAX1):c.428G>C (p.Gly143Ala)

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.428G>C (p.Gly143Ala)

HGVS:

NC_000001.11:g.154273885G>C
NG_007369.1:g.6323G>C
NM_001018837.2:c.284G>C
NM_006118.4:c.428G>CMANE SELECT
NP_001018238.1:p.Gly95Ala
NP_006109.2:p.Gly143Ala
NP_006109.2:p.Gly143Ala
LRG_64t1:c.428G>C
LRG_64:g.6323G>C
LRG_64p1:p.Gly143Ala
NC_000001.10:g.154246361G>C
NM_006118.3:c.428G>C

Protein change:

G143A

Links:

dbSNP: rs755031266

NCBI 1000 Genomes Browser:

rs755031266

Molecular consequence:

NM_001018837.2:c.284G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006118.4:c.428G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000825604	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 24, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19036076, 28492532
SCV001455154	Natera, Inc.	no assertion criteria provided	Likely benign (Jan 8, 2020)	germline	clinical testing
SCV003810659	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 20, 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

SCV000825604

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 24, 2022)

germline

clinical testing

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

SCV001455154

Natera, Inc.

no assertion criteria provided

Likely benign
(Jan 8, 2020)

germline

clinical testing

SCV003810659

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 20, 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

Homozygous HAX1 mutations in severe congenital neutropenia patients with sporadic disease: a novel mutation in two unrelated British kindreds.

Smith BN, Ancliff PJ, Pizzey A, Khwaja A, Linch DC, Gale RE.

Br J Haematol. 2009 Mar;144(5):762-70. doi: 10.1111/j.1365-2141.2008.07493.x. Epub 2008 Nov 22.

PubMed [citation]

PMID:: 19036076

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000825604.4

#	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 replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 143 of the HAX1 protein (p.Gly143Ala). This variant is present in population databases (rs755031266, gnomAD 0.07%). This missense change has been observed in individual(s) with severe congenital neutropenia (PMID: 19036076). ClinVar contains an entry for this variant (Variation ID: 574945). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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

From Natera, Inc., SCV001455154.1

#	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

From Revvity Omics, Revvity, SCV003810659.2

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

#	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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