ClinVar

Description

Variant summary: HBB c.430C>T [p.His144Tyr; also known as Hb Old Dominion/Burton-upon-Trent (OD/BuT) and as legacy name p.His143Tyr] results in a conservative amino acid change located in the Globin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.430C>T has been reported in the literature in multiple individuals with diabetes mellitus who were identified as having an abnormal hemoglobin that co-elutes with hemoglobinA1c, but had no other evidence of hemoglobinopathy (e.g. Elder_1998, Gilbert_2000, Plaseska-Karanfilska_2000). These findings indicate that the variant is unlikely to be associated with hemoglobin-related disease. The only potential clinical consequence that has been observed for this variant is that it co-elutes with HbAlc on ion exchange chromatography and thereby causes a spurious increase in HbAlc, compromising the utility of this test to monitor the treatment of diabetes mellitus in individuals with the variant. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant had a slight increase in oxygen affinity that did not appear to result in a clinical impact (e.g. Elder_1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.