NM_000517.6(HBA2):c.379G>A (p.Asp127Asn) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 10, 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:: RCV001284150.20

Allele description [Variation Report for NM_000517.6(HBA2):c.379G>A (p.Asp127Asn)]

NM_000517.6(HBA2):c.379G>A (p.Asp127Asn)

Genes:

LOC106804612:hemoglobin subunit alpha 2 recombination region [Gene]
HBA2:hemoglobin subunit alpha 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000517.6(HBA2):c.379G>A (p.Asp127Asn)

Other names:

D126N

HGVS:

NC_000016.10:g.173550G>A
NG_000006.1:g.34413G>A
NG_046165.1:g.3289G>A
NG_059186.1:g.1900G>A
NG_059271.1:g.5704G>A
NM_000517.6:c.379G>AMANE SELECT
NP_000508.1:p.Asp127Asn
LRG_1240t1:c.379G>A
LRG_1225:g.1900G>A
LRG_1240:g.5704G>A
LRG_1240p1:p.Asp127Asn
NC_000016.9:g.223549G>A
NM_000517.4:c.379G>A

Protein change:

D127N; ASP126ASN

Links:

OMIM: 141850.0037; dbSNP: rs33933481

NCBI 1000 Genomes Browser:

rs33933481

Molecular consequence:

NM_000517.6:c.379G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001157598	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Oct 10, 2022)	germline	clinical testing	Citation Link,
SCV001469776	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Sep 9, 2020)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 13856, 10490145, 7019159, 27240426, 26467025
SCV002024948	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2021)	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

SCV001157598

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Pathogenic
(Oct 10, 2022)

germline

clinical testing

Citation Link,

SCV001469776

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Sep 9, 2020)

unknown

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002024948

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 2, 2021)

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hemoglobin Tarrant: alpha126(H9) Asp leads to Asn. A new hemoglobin variant in the alpha1beta1 contact region showing high oxygen affinity and reduced cooperativity.

Moo-Penn WF, Jue DL, Johnson MH, Wilson SM, Therrell B Jr, Schmidt RM.

Biochim Biophys Acta. 1977 Feb 22;490(2):443-51.

PubMed [citation]

PMID:: 13856

The Hb Tarrant [alpha126(H9)Asp-->Asn]] mutation is localized in the alpha2-globin gene.

Perea FJ, Zamudio G, Meillon LA, Ibarra B.

Hemoglobin. 1999 Aug;23(3):295-7. No abstract available.

PubMed [citation]

PMID:: 10490145

See all PubMed Citations (6)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001157598.5

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

Description

The Hb Tarrant variant (HBA2: c.379G>A; p.Asp127Asn, also known as Asp126Asn when numbered from the mature protein, rs33933481, HbVar ID: 188) has been described in healthy individuals or individuals with mild erythrocytosis as a heterozygote and more severe erythrocytosis as a homozygote (Ibarra 1981, Ip 2016, HbVar database). The aspartate at residue 127 is located at the alpha1-alpha2 interface and forms salt bridges with Arg142 on the opposite dimer (Wajcman 2005). Variants in this region commonly lead to high oxygen affinity and reduced cooperativity (Wajcman 2005), which has been observed for the Hb Tarrant variant (Moo-Penn 1977). This variant is reported in ClinVar (Variation ID: 15662) and is found on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic dominant for mild erythrocytosis. References: Link to variant in HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Ibarra B et al. Heterozygosity and homozygosity for the high oxygen affinity hemoglobin Tarrant or alpha 126 (H9) Asp replaced by Asn in two Mexican families. Hemoglobin. 1981;5(4):337-48. PMID: 7019159. Ip KL et al. Hb Tarrant (a126(H9)Asp?Asn; HBA2: c.379G?>?A (or HBA1)) in a Chinese Family as a Cause of Familial Erythrocytosis. Hemoglobin. 2016 Aug;40(4):260-3. PMID: 27240426. Moo-Penn WF et al. Hemoglobin Tarrant: alpha126(H9) Asp leads to Asn. A new hemoglobin variant in the alpha1beta1 contact region showing high oxygen affinity and reduced cooperativity. Biochim Biophys Acta. 1977 Feb 22;490(2):443-51. PMID: 13856. Wajcman H et al. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin. 2005;29(2):91-106. PMID: 15921161.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469776.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant has been shown to be damaging to protein function(s) relevant to disease mechanism. The variant predicted to have a damaging effect on the protein.

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

From Revvity Omics, Revvity, SCV002024948.3

#	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: Aug 25, 2024

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