11-5227003-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PM1PM5PP5_Very_StrongBP4BS2_Supporting

The NM_000518.5(HBB):c.19G>A(p.Glu7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000736 in 1,611,030 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E7V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 6 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35B:1O:1

Conservation

PhyloP100: 2.63

Publications

116 publications found

Variant links:

Genes affected

HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

HBB Gene-Disease associations (from GenCC):

dominant beta-thalassemia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
hemoglobin M disease
Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
beta thalassemia
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
beta-thalassemia HBB/LCRB
Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
sickle cell disease and related diseases
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
erythrocytosis, familial, 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Heinz body anemia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
sickle cell disease
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
beta-thalassemia intermedia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
beta-thalassemia major
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
delta-beta-thalassemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin C disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin C-beta-thalassemia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin E disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin E-beta-thalassemia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-beta-thalassemia disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin c disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin d disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin E disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HBB links:

ENSG00000298932 (HGNC:):

ENSG00000298932 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 30 uncertain in NM_000518.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5227002-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 15333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 11-5227003-C-T is Pathogenic according to our data. Variant chr11-5227003-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.01455009). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 6 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000518.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	NM_000518.5	MANE Select	c.19G>A	p.Glu7Lys	missense	Exon 1 of 3	NP_000509.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HBB	ENST00000335295.4	TSL:1 MANE Select	c.19G>A	p.Glu7Lys	missense	Exon 1 of 3	ENSP00000333994.3
HBB	ENST00000485743.1	TSL:1	c.19G>A	p.Glu7Lys	missense	Exon 1 of 2	ENSP00000496200.1
HBB	ENST00000647020.1		c.19G>A	p.Glu7Lys	missense	Exon 1 of 3	ENSP00000494175.1

Frequencies

GnomAD3 genomes

AF:

0.00374

AC:

570

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000916

AC:

230

AN:

251156

AF XY:

0.000567

show subpopulations

Gnomad AFR exome

AF:

0.0134

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000422

AC:

615

AN:

1458696

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

273

AN XY:

725878

show subpopulations

African (AFR)

AF:

0.0159

AC:

532

AN:

33368

American (AMR)

AF:

0.000246

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1109158

Other (OTH)

AF:

0.000896

AC:

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00375

AC:

571

AN:

152334

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

265

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0134

AC:

556

AN:

41568

American (AMR)

AF:

0.000784

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00178

Hom.:

Bravo

AF:

0.00536

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0161

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00123

AC:

149

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:35Benign:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:13

Mar 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

Jun 07, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

Nov 29, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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)

Feb 27, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 01, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 06, 2025

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 15, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 16, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM5, PM1, PM3

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HBB: PM3:Very Strong, PS3:Moderate, PM2:Supporting, BP4

Apr 04, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 06, 2024

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the HBB gene demonstrated a sequence change, c.19G>A, in exon 1 that results in an amino acid change, p.Glu7Lys. This particular sequence change, also known as hemoglobin C (HbC), is a well-described pathogenic variant that has previously been described in the homozygous or compound heterozygous state (particularly with HbS, p.Glu7Val) in multiple unrelated individuals with sickle-hemoglobin C disease, hemoglobin C-beta thalassemia, and other beta-hemoglobinopathies (PMIDs: 23297836, 23591685, 27117572). This sequence change has been described in the gnomAD database with a frequency of 1.34% in the African/African-American subpopulation (dbSNP rs33930165) and is thought to be one of the most prevalent pathogenic variants associated with beta-hemoglobinopathies (PMID: 23591685). The p.Glu7Lys change affects a poorly conserved amino acid residue located in a domain of the HBB protein that is known to be functional. The p.Glu7Lys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies indicate that the p.Glu7Lys sequence change results in reduced hydrophobicity versus wild-type hemoglobin (PMIDs: 2888754). Taken together, the available evidence indicates that this sequence change is pathogenic.

Hb SS disease

Pathogenic:5Other:1

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 02, 2019

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

Feb 10, 2021

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

Dec 11, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.124%). Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015126 /PMID: 8294201). Different missense changes at the same codon (p.Glu7Ala, p.Glu7Gln, p.Glu7Met, p.Glu7Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015333, VCV000036301 /PMID: 19460936, 3267215, 6129204 /3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Jan 17, 2024

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBB c.19G>A (p.Glu7Lys), also known as p.Glu6Lys, missense variant results in the substitution of glutamic acid at amino acid position 7 with lysine. Across a selection of the available literature the c.19G>A variant has been identified in a compound heterozygous state in at least 24 individuals with sickle-hemoglobin C disease (PMID: 26287797; PMID: 26275168; PMID: 27756326; PMID: 28589738; PMID: 36106931). The highest frequency of this allele in the Genome Aggregation Database is 0.01342 in the African population (version 2.1.1) which includes one homozygote. Functional evidence demonstrates that the c.19G>A variant reduces the hydrophobicity of hemoglobin compared to wildtype (PMID: 2888754). Based on the available evidence, the c.19G>A (p.Gly7Lys) variant is classified as pathogenic for sickle-hemoglobin C disease.

beta Thalassemia

Pathogenic:4

Nov 15, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

Mar 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method: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.

HBB-related disorder

Pathogenic:2

Jan 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method: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. Based on these observations, we interpret this variant as pathogenic.

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

Beta-thalassemia HBB/LCRB

Pathogenic:2

Genomics And Bioinformatics Analysis Resource, Columbia University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Aug 22, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

alpha Thalassemia;C0002895:Hb SS disease;C0700299:Heinz body anemia;C1858990:Dominant beta-thalassemia;CN322236:Beta-thalassemia HBB/LCRB

Pathogenic:1

Sep 11, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Inborn genetic diseases

Pathogenic:1

Oct 13, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.19G>A (p.E7K) alteration is located in exon 1 (coding exon 1) of the HBB gene. This alteration results from a G to A substitution at nucleotide position 19, causing the glutamic acid (E) at amino acid position 7 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.1235% (349/282566) total alleles studied. The highest observed frequency was 1.34% (335/24966) of African/African American alleles, including 1 homozygote. This alteration results in the hemoglobin C (HbC) variant. The homozygous state of HbC only results in mild hemolytic anemia, while co-occurrence with another deleterious allele results in a clinically significant disorder (Nagel, 2003; Akinbami, 2016). This amino acid position is not well conserved in available vertebrate species. HbC is less soluble than wild-type hemoglobin (HbA) and tends to crystallize in red blood cells (RBCs), resulting in a decreased ability of RBCs to deform in capillaries and inducing hemolysis (Nagel, 2003). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

Inherited hemoglobinopathy

Pathogenic:1

Nov 10, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu7Lys variant in HBB (also known as HbC or p.Glu6Lys in the literature) is a well-described pathogenic variant that along with p.Glu7Val (HbS), is thought to be one of the most prevalent hemoglobin abnormalities (Cook 2013 PMID: 23297836, Piel 2013). In the heterozygous state, the p.Glu7Lys variant is associated with hemoglobin C trait and in the homozygous state this variant results in hemoglobin C disease (Charache 1967 PMID: 6061750, Piel 2013 PMID: 23591685, Cook 2013 PMID: 23297836). In the compound heterozygous state with a second HBB variant associated with abnormal hemoglobin, this variant results in other beta-hemoglobinopathies such as sickle-hemoglobin C disease (co-inheritance with HbS) and hemoglobin C-beta thalassemia (with β-thalassemia pathogenic variants; Piel 2013 PMID: 23591685, Cook 2013 PMID: 23297836, Boucher 2016 PMID: 27117572). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 15126) and has been identified in 1.3% (555/41446) of African American chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). However, this frequency is low enough to be consistent with a recessive carrier frequency, which has been estimated to be at 3.2% (1/31) in the African American population (Piel 2013 PMID: 23591685). In vitro functional studies provide some evidence that this variant affects the kinetic properties of the hemoglobin protein, reducing its overall hydrophobicity (Adachi 1987 PMID: 2888754). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta-hemoglobinopathies. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_supporting, PM5.

Sickle cell-hemoglobin C disease

Pathogenic:1

Sep 14, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

alpha Thalassemia;C0002895:Hb SS disease;C0005283:beta Thalassemia;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1841621:Fetal hemoglobin quantitative trait locus 1;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6

Pathogenic:1

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary persistence of fetal hemoglobin

Pathogenic:1

Oct 29, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 strong, PS4 strong, PM2 moderated, PM3 very strong

Heinz body anemia

Pathogenic:1

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

HEMOGLOBIN C

Pathogenic:1

Dec 02, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB

Pathogenic:1

Apr 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Malaria, resistance to

Benign:1

Dec 02, 2011

OMIM

Significance:protective

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.3

PhyloP100

2.6

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.45

Sift

Uncertain

0.015

Sift4G

Benign

0.41

Polyphen

0.0050

Vest4

0.83

MVP

0.95

MPC

0.037

ClinPred

0.046

GERP RS

5.2

PromoterAI

-0.033

Neutral

(source)

Varity_R

0.68

gMVP

0.52

Mutation Taster

=23/77

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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