ClinVar Miner

Submissions for variant NM_000517.6(HBA2):c.60del (p.His21fs)

gnomAD frequency: 0.00006  dbSNP: rs886041399
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000341094 SCV000329991 pathogenic not provided 2023-04-17 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16798638, 29627922, 22943743, 36567661, 14508795)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000341094 SCV000601221 pathogenic not provided 2023-04-05 criteria provided, single submitter clinical testing The HBA2 c.60del (p.His21Thrfs*29) frameshift variant (also known as CD19(-G)) causes the premature termination of HBA2 protein synthesis. In addition, it has been reported in the published literature in several newborns with visibly elevated Hb Bart’s levels and is described to lead to an alpha-thalassemia phenotype (PMID: 14508795 (2003)). The variant was also reported in a heterozygous individual having an alpha+ thalassemia trait phenotype (PMID: 30830998 (2019)). Therefore, the variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001275677 SCV004848828 pathogenic alpha Thalassemia 2022-11-03 criteria provided, single submitter clinical testing The p.His21ThrfsX29 variant in the HBA2 has been reported in several individuals with alpha thalassemia,both in the homozygous state or in th ecompound heterozygous state in trans with another pathogenic variant (Harteveld 2003 PMID: 14508795, Keikhaei 2018 PMID: 29627922). It has also been reported in ClinVar (Variation ID 280127) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 21 and leads to a premature termination codon 29 amino acids downstream. Loss of function of the HBA2 gene is an established disease mechanism in autosomal recessive alpha Thalassaemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha thalassemia. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_Strong.
Natera, Inc. RCV001275677 SCV001461035 pathogenic alpha Thalassemia 2020-09-16 no assertion criteria provided clinical testing

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