ClinVar

Description

Variant summary: HBA2 c.369C>A (p.His123Gln) results in a non-conservative amino acid change located in the Globin (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 248160 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Another variant resulting in the same amino acid change (c.369C>G) known as Hb Westmead has been reported in the literature in individuals affected with Alpha Thalassemia without strong evidence of causality, and this variant occurs frequently in mainland China (e.g. Xiong_2010, Jiang_2020). These reports do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20412082, 32436451). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, although the Hb Westmead variant was classified as uncertain significance (n=4) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.