ClinVar

Description

Variant summary: HBB c.4G>A (p.Val2Met; also known as Hb South Florida) results in a conservative amino acid change in the encoded protein sequence. Three 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 251128 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant is known to interfere with some methods of HbA1c determination and has been (falsely) reported in several carriers as elevated HbA1c, but without clinical evidence of any hematologic abnormality (Shah 1986, Aslanger 2013, Celebiler 2014, Canatan 2016). These data indicate that this variant does not produce any clinical symptoms in heterozygous state. According to our knowledge, only one compound heterozygous individual has been reported in the literature who carried a pathogenic variant (c.92+1G>A) for beta-0-thalassemia in trans, and presented with beta-thalassemia trait without clinical manifestations (Tan 2006, Tan 2009). Since compound heterozygosity for two pathogenic variants would result in a more severe phenotype, this report provides supportive evidence for a benign role (Tan 2009). Early reports demonstrated that the variant prevents the cleavage of the initiator methionine (Boissel 1985), but does not result in an unstable hemoglobin (Shah 1986). However, to our knowledge no other studies performed further functional characterization, thus allowing no convincing conclusions about the variant effect. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.