ClinVar Genomic variation as it relates to human health

Variant summary: HBB c.295G>A (p.Val99Met; also known as Hb Koln) results in a conservative amino acid change located in the Globin domain 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 251394 control chromosomes (gnomAD). c.295G>A has been reported in the literature in heterozygous and compound heterozygous individuals presenting with clinical symptoms of Hemoglobinopathy and was observed to co-segregate with disease in an autosomal dominant manner (Chan_2010, Galacteros_1989, Huang_2011, Miller_1971). The occurrence of unstable hemoglobin and the presence of increased levels of reticulocytosis and Heinz bodies in those carrying the variant was described by a few of these studies. Several reports described the variant as the most common unstable hemoglobin (e.g. Coleman_1995). These data indicate that the variant is very likely to be associated with disease. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The Hb Koln variant (HBB: c.295G>A; p.Val99Met, also known as Val98Met when numbered from the mature protein, rs33933298, HbVar ID: 448) is reported in the literature in multiple families diagnosed with mild hemolytic anemia, including several de novo cases, and is associated with Heinz body formation and splenomegaly (Hutchinson 1964, Jackson 1967, Jones, 1967, Landin 1994, Miller 1971, Stamatoyannopoulos 1981, HbVar database and references therein). Clinical symptoms are present in heterozygous individuals, and the variant co-segregates with disease in an autosomal dominant manner (Hutchinson 1964, Jackson 1967). In addition, this variant has been found in an individual with a beta(0) thalassemia variant who was reported to have almost pure Hb Koln in red blood cells and hemolytic anemia, but did not require blood transfusions or splenectomy (Galacteros 1989). This variant is listed in ClinVar (Variation ID: 15241), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Functional analyses of the variant protein show decreased stability and an increase in the formation of inclusion bodies in red blood cells (Jones 1967, Miller 1971). Based on available information, this variant is considered to be pathogenic. References: HbVar link for HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html Galacteros F et al. Hemoglobin Köln occurring in association with a beta zero thalassemia: hematologic and functional consequences. Blood. 1989 Jul;74(1):496-500. Hutchinson HE et al. Hereditary Heinz-body anaemia, thrombocytopenia, and haemogloblinopathy (Hb Koeln) in a Glasgow family. Br Med J. 1964 Oct 31;2(5417):1099-103. Jackson JM et al. A West Australian family with a haemolytic disorder associated with haemoglobin Koln. Br J Haematol. 1967 Jul;13(4):474-81. Jones RV et al. Koln haemoglobinopathy. Further data and a comparison with other hereditary Heinz body anaemias. Br J Haematol. 1967 May;13(3):394-408. Landin B et al. Haemoglobin Köln as de novo mutations in Sweden: diagnosis by PCR and specific enzymatic cleavage. Eur J Haematol. 1994 Mar;52(3):156-61. Miller DR et al. Hemoglobin Koln disease occurring as a fresh mutation: erythrocyte metabolism and survival. Blood. 1971 Dec;38(6):715-29.