Variant: NM_000517.6(HBA2):c.89T>C (p.Leu30Pro)

Version: 1.0
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CA125593

15651 (ClinVar)

Gene: HBA2 (HGNC:3040)

Condition: HBA2-related alpha thalassemia spectrum

Inheritance Mode: Autosomal recessive inheritance

UUID: 29bc99e3-6288-43e4-9650-419a4e857e56

Approved on: 2026/4/8

Published on: 2026/4/8

HGVS expressions

NM_000517.6(HBA2):c.89T>C (p.Leu30Pro)
NM_000517.6:c.89T>C
NC_000016.10:g.173001T>C
CM000678.2:g.173001T>C
NC_000016.9:g.223000T>C
CM000678.1:g.223000T>C
NC_000016.8:g.163000T>C
NG_000006.1:g.33864T>C
NG_059186.1:g.1351T>C
NG_059271.1:g.5155T>C
ENST00000251595.11:c.89T>C
ENST00000251595.10:c.89T>C
ENST00000397806.1:c.-2+43T>C
ENST00000482565.1:n.108T>C
ENST00000484216.1:n.58T>C
NM_000517.4:c.89T>C

Pathogenic

• Met criteria codes: PS4_Moderate PM3_Very Strong PM2_Supporting PP3 PP1_Strong

• Not Met criteria codes: PM1

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

Evidence submitted by expert panel

Hemoglobinopathy VCEP

The c.89T>C (p.Leu30Pro) variant in HBA2 is a missense variant with a minor allele frequency of 0.0000022 (1/446,884 alleles) in gnomAD v4.1, which is lower than the ClinGen Hemoglobinopathy VCEP threshold (<0.0001) for PM2_Supporting and therefore meets this criterion [PM2_P]. This variant has been detected in 9 individuals with a severe clinical phenotype characterized by HbH inclusions and requirements for transfusion and splenectomy. Total PM3 points are 8 [PM3_VS; PMID: 20854116; 29219637; 18473239]. It has also been reported to segregate with HbH disease in 8 affected individuals from 8 families. The number of unaffected segregations is 4, giving a LOD score of 5.32 [PP1_S; PMID:29219637; 9629496; 8136277; 23094635]. This variant has been reported in 10 unrelated individuals with a hematological phenotype consistent with α-thalassemia trait (reduced MCV, MCH [7*0.15=1.05] or reduced MCV and MCH with normal RBC count [3*0.2=0.6]), giving a total score of 1.65 [PS4_M; PMID: 29219637; 23094635; 8136277; 9629496]. The computational predictor REVEL (score 0.91; VCEP threshold >0.8) suggests that this variant impacts HBA2 function [PP3]. Overall, this variant is classified as a 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): PM3_VS, PP1_S, PS4_M, PP3, PM2_P

Met criteria codes

• PS4_Moderate: This variant has been reported in ten unrelated individuals meeting reduced MCV, MCH [7*0.15=1.05] or reduced MCV, MCH and normal RBC count [3*0.2=0.6]. Total score is 1.65 [PMID: 29219637; 23094635; 8136277; 9629496]
• PM3_Very Strong: This variant has been detected in 9 individuals with severe clinical phenotype characterized by HbH inclusions and need for transfusion and splenectomy. Of those individuals, 7 were compound heterozygous for the variant and a pathogenic variant and were confirmed in trans by family studies, and 2 individuals were homozygous for the variant. Total PM3 points are 8 [PMID: 20854116; 29219637; 18473239]
• PM2_Supporting: The minor allele frequency in gnomAD v4.1 is 0.0000022 (1/446884 alleles), which is lower than the ClinGen Hemoglobinopathy VCEP threshold <0.0001 for PM2_Supporting, and therefore meets this criterion [PM2_P].
• PP3: The computational predictor REVEL gives a score of 0.91, which is above the threshold of 0.8, evidence that correlates with impact to HBA2 function.
• PP1_Strong: The variant has been reported to segregate with disease in 8 affected family members from 8 families. The total number of unaffected segregations is 4. The LOD score is 5.32. PMID: 29219637: 2 families with homozygous probands with HbH disease, parents all tested and heterozygous carriers. LOD: 1.2 PMID: 23094635: family B: both parents heterozygous carriers, proband homozygous and 2 siblings are heterozygous carriers and one sibling without the variant. LOD: 0.98 family C: Homozygous proband, family pedigree structure is unclear. LOD: 0.6 PMID: 8136277: 3 Family A: proband with HbH disease comp het: Hb Agrinio-Hb TSaudi, Both parents tested, mother is carrier of Hb Agrinio. LOD: 0.6 Family D: proband with HbH disease comp het: Hb Agrinio-Hb TSaudi, Both parents tested, mother is carrier of Hb Agrinio. One sibling who has 2 normal alleles. LOD: 0.73 Family F: proband with HbH disease comp het: Hb Agrinio-Hb TSaudi, Both parents tested, mother is carrier of Hb Agrinio. LOD: 0.6 PMID: 9629496: 1 homozygous proband with HbH disease, parents tested. LOD: 0.6

Not Met criteria codes

• 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.