ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.295G>A (p.Val99Met) (rs33933298)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506341 SCV000603896 pathogenic not provided 2017-08-02 criteria provided, single submitter clinical testing The Hb Koln variant (c.295G>A, Val98Met) has been reported in multiple families diagnosed with mild hemolytic anemia, and associated with Heinz body formation and splenomegaly (Hutchinson 1964, Jackson 1967, Jones, 1967, Miller 1971, HbVar database and references therein). It is located at a methylated CpG dinucleotide, a frequent source of variation (Perutz 1990) and has been identified several times de novo (Landin 1994, Miller 1971, Stamatoyannopoulos 1981). Clinical symptoms are present in heterozygous individuals, and the variant co-segregates with the disorder in an autosomal dominant manner (Hutchinson 1964, Jackson 1967). In addition, it 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). Functional characterization of the hemoglobin variant shows decreased protein stability, and prone to formation of inclusion bodies in red blood cells (Jones 1967, Miller 1971). The variant is listed in the dbSNP variant database (rs28933076), and observed in the general population with an overall allele frequency of 0.006 percent (16/277132 alleles) in the Genome Aggregation Database. The valine at residue 98 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. REFERENCES Link to HbVar database for Hb Koln: Galacteros F et al. Hemoglobin Koln 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 Koln 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. Perutz MF et al. Frequency of abnormal human haemoglobins caused by C----T transitions in CpG dinucleotides. Boll Soc Ital Biol Sper. 1990 Sep;66(9):809-19. Stamatoyannopoulos G et al. De novo mutations producing unstable hemoglobins or hemoglobins M. I. Establishment of a depository and use of data to test for an association of de novo mutation with advanced parental age. Hum Genet. 1981;58(4):396-404.
Integrated Genetics/Laboratory Corporation of America RCV000016443 SCV000919454 pathogenic Hemoglobinopathy 2018-03-23 criteria provided, single submitter clinical testing 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 4.1e-06 in 246166 control chromosomes. The c.295G>A has been reported in the literature in multiple individuals affected with Hemoglobinopathy and segregated with disease in a families in an autosomal dominant manner, evidenced by increased levels of reticulocytosis, thermic instability, and the presence of Heinz bodies in those carrying the variant (Galacteros_1989; Huang_2011). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000016443 SCV000036711 pathogenic Hemoglobinopathy 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016446 SCV000036714 pathogenic Heinz body anemia 1995-03-01 no assertion criteria provided literature only

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