ClinVar Miner

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

gnomAD frequency: 0.00414  dbSNP: rs33930165
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Total submissions: 30
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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 2021-11-29 criteria provided, single submitter clinical testing One of the most prevalent abnormal hemoglobin variants globally, alongside hemoglobin S (Cook et al., 2013; Piel et al., 2013); When inherited along with a second HBB pathogenic variant, compound heterozygosity could also result in other clinically significant hemoglobinopathies 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); Published functional studies demonstrate the E7K variant reduces the overall hydrophobicity as compared to wild type hemoglobin (Adachi et al., 1987); Also referred to as E6K, due to alternate nomenclature; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8294201, 23297836, 2888754, 19429541, 20305663, 21228398, 13208767, 13293203, 2412615, 6061750, 25087612, 22975760, 23591685, 22028795, 27117572, 26372199, 28121068, 30604644, 31589614)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000224028 SCV000603913 pathogenic not provided 2023-11-27 criteria provided, single submitter clinical testing The Hb C variant (HBB: c.19G>A; p.Glu7Lys, also known as Glu6Lys when numbered from the mature protein, rs33930165, HbVar ID: 227) is a common pathogenic beta globin 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: https://globin.bx.psu.edu/hbvar/menu.html 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. PMID: 23297836.
Eurofins Ntd Llc (ga) RCV000224028 SCV000700666 pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing
Invitae RCV000224028 SCV000930769 pathogenic not provided 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 7 of the HBB protein (p.Glu7Lys). This variant is present in population databases (rs33930165, gnomAD 1.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with beta-hemoglobinopathies (PMID: 20301551, 23297836, 26372199, 27117572). This variant is also known as p.Glu6Lys and HbC. ClinVar contains an entry for this variant (Variation ID: 15126). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HBB protein function. Experimental studies have shown that this missense change affects HBB function (PMID: 2888754). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000576347 SCV001138223 pathogenic beta Thalassemia 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000202507 SCV001163297 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000576347 SCV001194071 pathogenic beta Thalassemia 2019-11-15 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.19G>A(E7K, aka Hb C) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with the hemoglobin C form of disease. Sources cited for classification include the following: PMID 23297836, 23297836, 19061217 and 2888754. Classification of NM_000518.4(HBB):c.19G>A(E7K, aka Hb C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000202507 SCV001445885 pathogenic Hb SS disease 2019-05-02 criteria provided, single submitter clinical testing This variant has been previously reported as a homozygous or compound heterozygous change in patients with Sickle Cell Disease, Hemoglobin C Variant (PMID: 23297836, 23591685). Functional studies have shown that this variant reduces the overall hydrophobicity as compared to wild type hemoglobin (PMID: 2888754). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.12% (349/282566) in the general population and 1.34% (335/24,966) in African populations. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.19G>A (p.Glu7Lys) variant is classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000224028 SCV001450181 pathogenic not provided 2018-04-04 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000224028 SCV001714971 pathogenic not provided 2019-10-17 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001535943 SCV001752603 pathogenic Dominant beta-thalassemia; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; beta Thalassemia; Methemoglobinemia, beta-globin type; Erythrocytosis, familial, 6 2021-06-30 criteria provided, single submitter clinical testing
H3Africa Consortium RCV001777140 SCV002014638 benign not specified 2020-10-28 criteria provided, single submitter research While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.083, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error.
Revvity Omics, Revvity Omics RCV000224028 SCV002024963 pathogenic not provided 2023-02-09 criteria provided, single submitter clinical testing
DASA RCV001813746 SCV002061274 pathogenic Heinz body anemia 2022-01-05 criteria provided, single submitter clinical testing The c.19G>A;p.(Glu7Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 15126; PMID: 2030155; 27117572; 26372199; 23297836; 19061217; 30604644; 33091040) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 15973412) - PS3_supporting. The variant is present at low allele frequencies population databases (rs33930165– gnomAD 0.03745%; ABraOM 0.002989 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Glu7Lys) was detected in trans with a pathogenic variant (PMID: 27117572; 26372199; 23297836; 19061217; 30604644; 33091040) - PM3_very strong The variant co-segregated with disease in multiple affected family members (PMID: 4746100; 13908956) - PP1_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000224028 SCV002061510 pathogenic not provided 2021-08-16 criteria provided, single submitter clinical testing PS3, PM5, PM1, PM3
New York Genome Center RCV000202507 SCV002097813 pathogenic Hb SS disease 2021-02-10 criteria provided, single submitter clinical testing The c.19G>A, p.Glu7Lys variant in the HBB gene has been previously reported as a homozygous or compound heterozygous change in patients with Sickle Cell Disease, Hemoglobin C Variant [PMID: 23297836; PMID: 23591685]. Functional studies have shown that this variant reduces the overall hydrophobicity as compared to wild type hemoglobin [PMID:2888754]. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.12% (349/282566) in the general population and 1.34% (335/24,966) in African populations. This variant is an established disease-associated mutation and has been reported as pathogenic by multiple clinical diagnostic laboratories in ClinVar (variant ID: 15126). Based on the available evidence, the c.19G>A (p.Glu7Lys) variant is classified as Pathogenic.
MGZ Medical Genetics Center RCV002288494 SCV002581795 pathogenic Beta-thalassemia HBB/LCRB 2022-08-22 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000224028 SCV002585313 pathogenic not provided 2022-08-01 criteria provided, single submitter clinical testing HBB: PM3:Strong, PM5, PP1:Moderate, PS3:Moderate, PM2:Supporting, BP4
Ambry Genetics RCV002415418 SCV002721806 pathogenic Inborn genetic diseases 2017-01-24 criteria provided, single submitter clinical testing The p.E7K pathogenic mutation (also known as c.19G>A and E6K), located in coding exon 1 of the HBB gene, results from a G to A substitution at nucleotide position 19. The glutamic acid at codon 7 is replaced by lysine, an amino acid with similar properties. This mutation codes for hemoglobin C (Hb C), one of the most prevalent abnormal hemoglobins in human. Hb C is less soluble than wild-type hemoglobin (Hb A) and tends to crystallize in red blood cells (RBCs), resulting in a decreased ability of RBCs to deform in capillaries and inducing hemolysis (Nagel RL et al. Blood Rev., 2003 Sep;17:167-78). The homozygous state of Hb C only results in mild hemolytic anemia, while co-occurrence with another deleterious allele results in a clinically significant disorder (Nagel RL et al. Blood Rev., 2003 Sep;17:167-78). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV003137529 SCV003807059 pathogenic Hereditary persistence of fetal hemoglobin 2022-10-29 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 strong, PS4 strong, PM2 moderated, PM3 very strong
Johns Hopkins Genomics, Johns Hopkins University RCV003150807 SCV003839040 pathogenic Sickle cell-hemoglobin C disease 2022-09-14 criteria provided, single submitter clinical testing This HBB variant (rs33930165) reaches polymorphic frequency (>1%) within the African/African American subpopulation in a large population dataset (gnomAD: 335/24966 total alleles, 1.342%, 1 homozygote) and has been reported in ClinVar. Also known as p.Glu6Lys and HbC, it has been reported in a homozygous or compound heterozygous state in individuals with beta-hemoglobinopathies. Heterozygosity for p.Glu7Lys in the absence of another pathogenic HBB variant results in Hemoglobin C trait (HbAC), which is clinically silent. Two bioinformatic tools queried predict that this substitution would tolerated, but experimental studies have shown that this variant affects the physical and kinetic properties of the hemoglobin protein. Bioinformatic analysis predicts that this missense variant would not affect normal exon 1 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.19G>A (p.Glu7Lys) to be pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV003335041 SCV004046376 pathogenic HBB-Related Disorders criteria provided, single submitter clinical testing The c.19G>A (p.Glu7Lys, also known as p.Glu6Lys) variant in HBB is referred to as the hemoglobin C allele (HbC), and causes autosomal recessive hemoglobin C disease when it is homozygous or sickle-hemoglobin C disease when it is compound heterozygous with a hemoglobin S allele (PMID: 20301551, 26372199, 23297836, 27117572). Experimental studies showed that this variant affected the kinetic properties of the hemoglobin protein (PMID: 2888754). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.1% (349/282566). Based on the available evidence, the c.19G>A (p.Glu7Lys) variant is classified as Pathogenic.
Preventiongenetics, part of Exact Sciences RCV003398524 SCV004105930 pathogenic HBB-related condition 2022-10-19 criteria provided, single submitter clinical testing The HBB c.19G>A variant is predicted to result in the amino acid substitution p.Glu7Lys. This variant (reported as Glu6Lys) has been identified in the homozygous and compound heterozygous states in individuals with hemoglobin C disease, and is considered one of the most common hemoglobin abnormalities in the United States (Cook et al. 2013. PubMed ID: 23297836). In silico analysis showed that this variant possibly disrupts contact with other molecules as well as interfere with interaction with other regions of the protein (Alanazi et al. 2011. PubMed ID: 22028795). This variant has been observed in >1% of individuals of African ancestry, including 1 homozygote, in a large population database (http://gnomad.broadinstitute.org/variant/11-5248233-C-T). Based on these observations, we interpret this variant 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 not provided Hb SS disease no assertion provided literature only
Reproductive Health Research and Development, BGI Genomics RCV000576347 SCV001142415 pathogenic beta Thalassemia 2020-01-06 no assertion criteria provided curation NM_000518.4:c.19G>A is also known as p.Glu6Lys or HbC in the literature. NM_000518.4:c.19G>A in the HBB gene has an allele frequency of 0.013 in African subpopulation in the gnomAD database. Boucher et al. reported Mild Microcytic Anemia in an Infant with a compound heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB:c.157G > A) (PMID: 27117572). In addition, this variant was reported as the most common emoglobin (Hb) abnormality identified in the United States (PMID: 23297836). Experimental studies have shown that this variant affects the kinetic properties of the hemoglobin protein (PMID: 2888754). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PS3; PM3; PP4.
Natera, Inc. RCV000576347 SCV002091616 pathogenic beta Thalassemia 2017-03-17 no assertion criteria provided clinical testing
Genomics And Bioinformatics Analysis Resource, Columbia University RCV002288494 SCV004024143 pathogenic Beta-thalassemia HBB/LCRB no assertion criteria provided research

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