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.-78A>C

CA125328

15470 (ClinVar)

Gene: HBB (HGNC:3043)

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

Inheritance Mode: Autosomal recessive inheritance

UUID: 16667374-bf76-4afd-a940-8aa7726825fd

Approved on: 2026-04-07

Published on: 2026-04-07

HGVS expressions

NM_000518.5(HBB):c.-78A>C

NC_000011.10:g.5227099T>G

CM000673.2:g.5227099T>G

NC_000011.9:g.5248329T>G

CM000673.1:g.5248329T>G

NC_000011.8:g.5204905T>G

NG_000007.3:g.70517A>C

NG_059281.1:g.4973A>C

ENST00000647020.1:c.-78A>C

ENST00000380315.2:c.-18-60A>C

Pathogenic

PM1 PM5 PM3_Strong PS4_Very Strong PS3_Supporting PM2_Supporting PP3

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 HBB Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hemoglobinopathy VCEP

This variant (NM_000518.5: HBB:c.-78A>C) resides in a region, c.-80 to c.-76 (TATAA box), of HBB that is defined as a mutational hotspot and critical functional domain by the ClinGen Hemoglobinopathy VCEP [PM1]. It has been detected in three individuals with beta thalassemia major. These individuals are compound heterozygous for the variant (c.-78A>C) and a pathogenic variant (c.118C>T; c.36del and c.92+1G>A), confirmed in trans by family testing; total PM3 score is 3 [PM3_S; PMID 19960060; 8619407; Molecular Genetics Laboratory, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences; ClinVar IDs: 15402; 15423 and 15436]. It has also been reported in 13 unrelated individuals with low MCV (67-77.8 fl), low MCH (20.5-25.9 pg) and increased HbA2 (4.6-6.3%), and in 2 unrelated individuals with just low MCV (58.1 and 70 fl) and low MCH (18.2 and 23.3 pg); total score is 16.3 [PS4_VS; PMID 19960060; 8619407; Molecular Genetics Laboratory, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences; Department of Medical Genetics, National and Kapodistrian University of Athens; BGI Genomics]. In vitro transcriptional assay and transient expression assay showed 2- to 3-fold decrease in beta globin transcription indicating that this variant impacts protein function [PS3_P; PMID: 2987224]. Kinetic studies showed reduced association rate constant and increase dissociation constant of the TATA binding protein (TBP)/TATA box complex, also indicating that this variant impacts protein function (PMID: 24616209). The computational predictor CADD PHRED score 19.52 (above threshold >12) indicates that this variant impacts HBB function [PP3]. The minor allele frequency in gnomAD v4.1 is 0.000002948 (3/1017550) alleles, which is lower than the ClinGen Hemoglobinopathy VCEP threshold <0.0001 for PM2_Supporting, and therefore meets this criterion [PM2_P]. Another single nucleotide variant c.-78A>G (ClinVar ID: 15471) in the same base position is considered to have valid evidence for pathogenicity by the VCEP (PMID: 36453528) and has been classified as pathogenic for beta thalassemia with a 2-star review status by ClinVar [PM5]. 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): PS4_VS, PM3_S, PM5, PM1, PM2_P, PS3_P, PP3.

PM1

This variant resides in a region c.-80 to c.-76 (TATAA box), of HBB that is defined as a mutational hotspot and critical functional domain by the ClinGen Hemoglobinopathy VCEP

PM5

Another single nucleotide variant c.-78A>G (ClinVar ID: 15471) in the same base position is considered to have valid evidence for pathogenicity by the VCEP and has been classified as pathogenic for beta thalassemia with a 2-star review status by ClinVar

PM3_Strong

This variant has been detected in three individuals with beta thalassemia/major. These individuals are compound heterozygous for the variant (c.78A>C) and pathogenic beta thalassemia and related diseases variants (c.118C>T; c.36del and C.92+1G>A), and were confirmed in trans by family testing. Total PM3 score is 3 (PMID 19960060; PMID: 8619407; internal lab database; ClinVar IDs: 15402; 15423 and 15436) PMID 19960060: In Trans with pathogenic c.118C>T, p.Gln40Ter (CD 39 C>T): Two stars in ClinVar (ID: 15402): exempt from PM2 requirement PMID: 8619407: In Trans with pathogenic c.36del, p.Thr13fs (CD 11 (-T): Two stars in ClinVar (ID: 15423): rare in gnomAD Internal lab database contribution: In trans with pathogenic C.92+1G>A (IVS I-1 G-A): Two stars in ClinVar (ID: 15436): exempt from PM2 requirement.

PS4_Very Strong

This variant has been reported in 13 unrelated individuals with low mcv (67-77.8), low mch (20.5-25.9), and increased HbA2 (4.6-6.3), and in 2 individuals with just low MCV (58.1 and 70) and low MCH (18.2 and 23.3): Total score is 16.3 (PMID 19960060; PMID: 8619407; Internal Lab database) PMID 19960060; PMID: 8619407: 2 individuals with low MCV (69 and 69.9), low MCH (21.8 and 20.5) and increased HbA2 (4.8 and 5): 2x1.5=3 Internal lab database contribution: 11 individuals with low MCV (67-77.8), low MCH (20.5-25.9) and increased HbA2 (4.6-6.3): 11x1.5=16.5=max score is 16 2 individuals with low MCV (58.1 and 70), low MCH (18.2 and 23.3): 2x0.15=0.3

PS3_Supporting

In vitro transcriptional assay and transient expression assay showed 2- to 3-fold decrease in beta globin transcription indicating that this variant impacts protein function (PMID: 2987224). Kinetic studies showed reduced association rate constant and increase dissociation constant of the TATA binding protein (TBP)/TATA box complex also indicating that this variant impacts protein function (PMID: 24616209)

PM2_Supporting

The minor allele frequency in gnomAD v4.1 is 0.000002948 (3/1017550) 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 CADD gives a PHRED score of 19.52, which is above threshold >12, evidence that correlates with impact to HBB function.

PP1

The variant has been reported to segregate with disease in 1 affected family member from one family. The total number of unaffected segregations is 0. The LOD score is 0.6 (PMID: 8619407).

Curation History

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