Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000518.5(HBB):c.82G>T (p.Ala28Ser)

CA124983

15239 (ClinVar)

Gene: HBB (HGNC:3043)

Condition: beta-thalassemia HBB/LCRB (MONDO:0013517)

Inheritance Mode: Autosomal recessive inheritance

UUID: 23a1f723-f975-46ee-b42a-01ececf77079

Approved on: 2026-04-07

Published on: 2026-04-07

HGVS expressions

NM_000518.5(HBB):c.82G>T (p.Ala28Ser)

NM_000518.5:c.82G>T

NC_000011.10:g.5226940C>A

CM000673.2:g.5226940C>A

NC_000011.9:g.5248170C>A

CM000673.1:g.5248170C>A

NC_000011.8:g.5204746C>A

NG_000007.3:g.70676G>T

NG_059281.1:g.5132G>T

ENST00000647020.1:c.82G>T

ENST00000335295.4:c.82G>T

ENST00000380315.2:c.82G>T

ENST00000485743.1:n.133G>T

ENST00000633227.1:c.76+6G>T

NM_000518.4:c.82G>T

Pathogenic

PP1_Strong PS3_Supporting PS4_Moderate PP3 PM3 PM2_Supporting

PM5

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 HBB Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hemoglobinopathy VCEP

The c.82G>T (p.Ala28Ser) variant is located in the HBB gene. This variant has been reported in 12 unrelated individuals displaying a hematological phenotype consistent with beta thalassemia trait (reduced MCV and MCH with normal or increased RBC count), giving a total score of 2.15 [PS4_M; PMID: 7104238; 3955238; The Hemoglobinopathies Laboratory, Department of Human and Clinical Genetics, Leiden University Medical Center; Department of Medical Genetics, National and Kapodistrian University of Athens]. This variant has been reported to segregate with a beta-thalassemia intermedia phenotype in 8 affected family members from 4 families. The total number of unaffected segregations is 8 with a LOD score of 5.81 [PP1_S; PMID:7104238; 3955238; 25332589; 30777047; 17949282]. It was detected in combination with a pathogenic variant in one affected individual, confirmed in trans by DNA studies, and found in a homozygous state in another, both presenting with a beta-thalassemia intermedia phenotype. Total PM3 points are 1.5 [PM3; PMID:3955238; 25332589; Variation ID: 15438]. Hemoglobin biosynthesis assay showed a change in biosynthetic ratio of globins in a heterozygous sample (β/α ratio 0.45-0.55), indicating that this variant impacts protein function. In addition, in vitro splicing assay showed that this variant leads to abnormal RNA processing by creating/utilizing a cryptic splice site in exon 1 of HBB [PS3_P; PMID:6733281; 7104238; 7173395]. The computational predictor SpliceAI gives a Δ score of 0.79 for donor gain in exon 3, which is above the VCEP threshold >0.3, predicting that this variant may affect splicing by disrupting the donor splice site of intron 3 in HBB [PP3]. The minor allele frequency in gnomAD v4.1 is 0.000002479 (4/1613406) 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 pathogenic for beta thalassemia (MONDO:0013517) in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen Hemoglobinopathy VCEP (specification version 1.0.0): PP1_S, PS4_M, PM3, PM2_P, PP3, PS3_P.

PP1_Strong

The variant has been reported to segregate with [beta thalassemia ] in [8] affected family members from [4] families. The total number of unaffected segregations is [8]. The LOD score is [5.81] [PMIDs:7104238; 3955238; 25332589; 30777047;17949282]

PS3_Supporting

Globin biosynthesis showed an β/α ratio to be between 0.45-0.55 indicating that this variant impacts protein function [PMID: 7104238 and PMID:7173395]. [In vitro spicing assay] demonstrated that the variant impacts splicing by [ creating a cryptic donor region of exon 1] [PMID:6733281].

PS4_Moderate

This variant has been reported in [12] unrelated probands meeting [beta thalassemia trait]. Total score is 2.15 [PMID: 7104238, PMID:3955238 and internal lab contributors].

PP3

The computational predictor SpliceAI gives a Δ score of 0.79 for donor gain in exon 3, which is above threshold >0.3, predicting that the variant may affect splicing by disrupting the donor splice site of intron 3 in HBB.

PM3

This variant has been detected in 2 individuals with a beta-thalassemia intermedia phenotype. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic variant (β0 IVSII-I G>C), confirmed in trans by family testing and DNA studies, and the other was homozygous for the variant. Total PM3 points: 1.5 [PMID:3955238, PMID:25332589; VCV000015438.38].

PM2_Supporting

The minor allele frequency in gnomAD v4.1 is 0.000002479 (4/1613406) alleles, which is lower than the ClinGen Hemoglobinopathy VCEP threshold <0.0001 for PM2_Supporting, and therefore meets this criterion.

PM5

Two different missense variants [c.83C>T (p.Ala28Val); c.83C>A (p.Ala28Asp)] in the same codon have been reported in patients with haemoglobinopathy [VCV000015184.2; VCV000015386.3]. However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen Hemoglobinopathy VCEP/(or) with a 2-star review status by ClinVar.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.