Evidence Repository - Clinical Genome Resources

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Variant: NM_000517.6(HBA2):c.377T>G (p.Leu126Arg)

CA125658

15690 (ClinVar)

Gene: HBA2 (HGNC:3040)

Condition: HBA2-related alpha thalassemia spectrum (MONDO:0100562)

Inheritance Mode: Autosomal recessive inheritance

UUID: 1e6dcef7-360e-4f30-ab5c-a3383e00a026

Approved on: 2026-04-08

Published on: 2026-04-08

HGVS expressions

NM_000517.6:c.377T>G

NM_000517.6(HBA2):c.377T>G (p.Leu126Arg)

NC_000016.10:g.173548T>G

CM000678.2:g.173548T>G

NC_000016.9:g.223547T>G

CM000678.1:g.223547T>G

NC_000016.8:g.163547T>G

NG_000006.1:g.34411T>G

NG_059186.1:g.1898T>G

NG_059271.1:g.5702T>G

ENST00000251595.11:c.377T>G

ENST00000251595.10:c.377T>G

ENST00000397806.1:c.281T>G

ENST00000482565.1:n.513T>G

NM_000517.4:c.377T>G

Likely Pathogenic

PM3 PS4_Moderate PM2_Supporting PP3

PM1 PM5 BP4 PP1

Evidence Links 0

Expert Panel

Hemoglobinopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBA2 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hemoglobinopathy VCEP

The NM_000517.6(HBA2):c.377T>G variant in HBA2 is a missense variant predicted to cause substitution of leucine by arginine at amino acid 125 (p.Leu126Arg). This variant has been reported in at least 8 unrelated individuals with an α-thalassaemia trait phenotype (low MCV and MCH with normal/increased RBC count) [PS4_M; PMID:15921163;23368878; The Hemoglobinopathies Laboratory, Department of Human and Clinical Genetics, Leiden University Medical Center; Molecular Genetics Laboratory, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences]. It has also been detected in two homozygous individuals with moderate anemia, microcytosis and hypochromia, with one requiring transfusion therapy. Total PM3 points are 1 [PM3; PMID: 21077766; Molecular Genetics Laboratory, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences]. The computational predictor REVEL (score 0.843; VCEP threshold >0.8) suggests that this variant impacts HBA2 function [PP3]. There is no detection of abnormal Hb protein and globin chain by electrophoretic techniques (e.g., IEF, electrophoresis on citrate agar and ion exchange HPLC) and reversed-phase HPLC, respectively, while the isopropanol precipitation test for Hb stability is negative. The minor allele frequency in gnomAD v4.1 is 0.0000031 (5/1607758 alleles), which is lower than the ClinGen Hemoglobinopathy VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets this criterion [PM2_P]. In summary, this variant meets the criteria to be classified as a likely pathogenic variant for recessive HBA2-related alpha thalassemia spectrum (MONDO:0100562) based on the ACMG/AMP criteria applied, as specified by the ClinGen Hemoglobinopathy VCEP (specification version 1.0.0): PS4_M, PM3, PP3, PM2_P.

PM3

This variant has been detected in 2 individuals with an α-thalassaemia diagnosis. Both were homozygous for the variant. Total PM3 points are 1. [PMID: 21077766; internal laboratory data].

PS4_Moderate

This variant has been reported in at least 8 unrelated probands with an α-thalassaemia trait phenotype meeting reduced red cell indices (MCV <79 fl, MCH <27 pg) with normal/increased red blood cell count. Total points 1.6 [PMID:15921163; PMID:23368878; Internal lab collaborators].

PM2_Supporting

The minor allele frequency in gnomAD v4.1 is 0.0000031 (5/1607758 alleles), which is lower than the ClinGen Hemoglobinopathy VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets this criterion

PP3

The computational predictor REVEL gives a score of 0.843, which is above the threshold of 0.8, evidence that correlates with impact to HBA2 function.

PM1

This variant does not reside within a region of HBA2 that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Hemoglobinopathy VCEP. According to literature, residue α125 is located in helix H and is critical for the α1β1 contact. Replacement of the non-polar Leu residue by the positively charged Arg residue changes the α1β1 contact and, therefore, the dimer formation is impaired.

PM5

2 different missense variants [NM_000517.6(HBA2):c.377T>A (p.Leu126Gln), no-star P in ClinVar; NM_000517.6(HBA2):c.377T>C (p.Leu126Pro), one-star P in ClinVar] in the same codon have been reported in patients with alpha thalassemia [VCV000869221.1; VCV000015630.3]. However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Hemoglobinopathy VCEP/(or) with a 2 star review status by ClinVar.

BP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP1

The variant has been reported to segregate with a more severe phenotype compared to both variants in isolation in 1 affected family member from 1 family. The total number of unaffected segregations is 0. The LOD score is 0.6 [internal laboratory data]

Curation History

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