Submissions for variant NM_000517.6(HBA2):c.428A>C (p.Ter143Ser)

dbSNP: rs41321345

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759055	SCV000888136	pathogenic	not provided	2022-08-03	criteria provided, single submitter	clinical testing	This variant disrupts the translation stop codon of the HBA2 mRNA and is predicted to cause HBA2 protein elongation. The frequency of this variant in the general population, 0.000004 (1/248882 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been associated with alpha-thalassemia (PMIDs: 26365411 (2015), 19373587 (2009), 1802886 (1991), 1155453 (1975)). Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759055	SCV002048664	pathogenic	not provided	2021-09-18	criteria provided, single submitter	clinical testing	The Hb Koya Dora variant (HBA2: c.428A>C; p.Ter143SerextTer31 also known as Ter142Ser when numbered from the mature protein, rs41321345) is reported in the heterozygous state associated with mild anemia and hypochromia (see link to HbVar). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant abolishes the canonical termination codon, resulting in an elongated protein that is unstable, similar to other stop loss variants (Hb Constant Spring, Hb Icaria)(see HbVar links and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database for Hb Koya Dora: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=705&.cgifields=histD Link to HbVar database for Hb Constant Spring: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=703&.cgifields=histD Link to HbVar database for Hb Icaria: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=704&.cgifields=histD
Neuberg Centre For Genomic Medicine, NCGM	RCV004546413	SCV005042651	likely pathogenic	alpha Thalassemia		criteria provided, single submitter	clinical testing	The stop lost c.428A>C p.Ter143SerextTer31 variant in the HBA2 gene has been reported in compound heterozygous state in a patient with Alpha-thalassemia Deshpande, Prashant et al., 2015. This variant is reported with the allele frequency 0.0004% in the gnomAD Exomes and novel in 1000 Genomes. The variant is reported to ClinVar as Pathogenic. The p.Ter143SerextTer31 variant in the stop codon Ter/* at position 143, changing it to a Serine-codon a no-stop variant and adding a tail of new amino acids to the protein’s C-terminus, ending at a new stop codon Ter/* at position 31. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. The amino acid change p.Ter143SerextTer31 in HBA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Functional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005007856	SCV005642325	pathogenic	Heinz body anemia; alpha Thalassemia; Hemoglobin H disease; Erythrocytosis, familial, 7	2024-06-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000759055	SCV005872914	likely pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
OMIM	RCV000016894	SCV000037165	other	HEMOGLOBIN KOYA DORA	2013-03-28	no assertion criteria provided	literature only