ClinVar Genomic variation as it relates to human health

The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant has been shown to be damaging to protein function(s) relevant to disease mechanism. The variant predicted to have a damaging effect on the protein.

The Hb Tarrant variant (HBA2: c.379G>A; p.Asp127Asn, also known as Asp126Asn when numbered from the mature protein, rs33933481, HbVar ID: 188) has been described in healthy individuals or individuals with mild erythrocytosis as a heterozygote and more severe erythrocytosis as a homozygote (Ibarra 1981, Ip 2016, HbVar database). The aspartate at residue 127 is located at the alpha1-alpha2 interface and forms salt bridges with Arg142 on the opposite dimer (Wajcman 2005). Variants in this region commonly lead to high oxygen affinity and reduced cooperativity (Wajcman 2005), which has been observed for the Hb Tarrant variant (Moo-Penn 1977). This variant is reported in ClinVar (Variation ID: 15662) and is found on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic dominant for mild erythrocytosis. References: Link to variant in HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Ibarra B et al. Heterozygosity and homozygosity for the high oxygen affinity hemoglobin Tarrant or alpha 126 (H9) Asp replaced by Asn in two Mexican families. Hemoglobin. 1981;5(4):337-48. PMID: 7019159. Ip KL et al. Hb Tarrant (a126(H9)Asp?Asn; HBA2: c.379G?>?A (or HBA1)) in a Chinese Family as a Cause of Familial Erythrocytosis. Hemoglobin. 2016 Aug;40(4):260-3. PMID: 27240426. Moo-Penn WF et al. Hemoglobin Tarrant: alpha126(H9) Asp leads to Asn. A new hemoglobin variant in the alpha1beta1 contact region showing high oxygen affinity and reduced cooperativity. Biochim Biophys Acta. 1977 Feb 22;490(2):443-51. PMID: 13856. Wajcman H et al. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin. 2005;29(2):91-106. PMID: 15921161.

Variant summary: HBA2 c.379G>A (p.Asp127Asn) results in a conservative amino acid change located in the globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248750 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.379G>A has been reported in the literature in five families with several heterozygous individuals who were clinically asymptomatic with mild erythrocytosis on hemoglobin analysis and one homozygous individual whose only hematologic finding was moderate erythrocytosis by hemoglobin analysis (e.g. Schroeder_1982, Moo-Penn_1977, Ibarra_1981, Ip_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. At least one publication reports that this variant results in increased oxygen affinity and low cooperativity (e.g. Moon-Penn_1977). This variant is also known as HB Tarrant. The following publications have been ascertained in the context of this evaluation (PMID: 7019159, 27240426, 13856, 7092797). ClinVar contains an entry for this variant (Variation ID: 15662). Based on the evidence outlined above, the variant was classified as uncertain significance for alpha thalassemia.