ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.19G>A (p.Glu7Lys) (rs33930165)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224028 SCV000280895 pathogenic not provided 2014-09-15 criteria provided, single submitter clinical testing
GeneDx RCV000224028 SCV000321759 pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing The E7K (also referred to as E6K, due to alternate nomenclature) pathogenic variant results in HbC, a structural variant of normal hemoglobin. It is one of the most prevalent abnormal hemoglobin variants globally alongside hemoglobin S (Cook et al., 2013; Piel et al., 2013). E7K has been reported in the homozygous state, or compound heterozygous state, along with a second hemoglobin variant, in numerous individuals with hemoglobin C disease (Cook et al., 2013). When inherited along with a second HBB pathogenic variant, compound heterozygosity could also result in other clinically significant hemoglobinopathis such as sickle-hemoglobin C disease and hemoglobin C-beta thalassemia (Piel et al., 2013). HbC allele frequencies above 15% have been described in West African populations, and the estimated carrier frequency for HbC in the African American population is 1/31 (Piel et al., 2013; Tabor et al., 2014). The E7K variant is a non-conservative amino acid substitution, which occurs at a position that is not conserved across species. Functional studies have shown that the E7K variant reduces the overall hydrophobicity as compared to wild type hemoglobin (Adachi et al., 1987). In silico analysis predicts that E7K shows a difference in charge that will disturb the ionic interaction of the original wild type residue, which could possibly disrupt contacts with other molecules as well as disturb the interaction with the other parts of the protein (Alanzai et al., 2011). We interpret E7K as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000224028 SCV000603913 pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing The Hb C variant (HBB: c.19G>A, Glu6Lys) is a common pathogenic beta globin (HBB) variant. Heterozygosity is consistent with Hb C trait. Homozygosity is consistent with a clinical presentation of mild to moderate hemolytic anemia with mild microcytosis and frequent target cells. Hb C in combination with a beta thalassemia variant on the opposite chromosome is often associated with mild microcytic anemia (Cook 2013, HbVar database). REFERENCES Link to HbVar database for Hb C: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=227 Cook C et al. The clinical and laboratory spectrum of Hb C [beta6(A3)Glu>Lys, GAG>AAG] disease. Hemoglobin. 2013; 37(1):16-25.
Counsyl RCV000576347 SCV000678039 pathogenic beta Thalassemia 2015-07-29 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224028 SCV000700666 pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing
Invitae RCV000224028 SCV000930769 pathogenic not provided 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 7 of the HBB protein (p.Glu7Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs33930165, ExAC 1.4%). This is a common, well-known variant that has been observed in individuals affected with beta-hemoglobinopathies (PMID: 20301551, 26372199, 23297836, 27117572). It is also known as p.Glu6Lys and HbC in the literature. ClinVar contains an entry for this variant (Variation ID: 15126). Experimental studies have shown that this variant affects the kinetic properties of the hemoglobin protein (PMID: 2888754). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016284 SCV000036552 pathogenic HEMOGLOBIN C 2011-12-02 no assertion criteria provided literature only
OMIM RCV000016285 SCV000036553 protective Malaria, resistance to 2011-12-02 no assertion criteria provided literature only
GeneReviews RCV000202507 SCV000190689 pathogenic Hb SS disease 2014-10-23 no assertion criteria provided literature only

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