Submissions for variant NM_000518.5(HBB):c.20A>T (p.Glu7Val)

gnomAD frequency: 0.01298  dbSNP: rs334

Total submissions: 58

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000224000	SCV000224235	pathogenic	not provided	2014-12-19	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224000	SCV000281507	pathogenic	not provided	2014-09-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000224000	SCV000321760	pathogenic	not provided	2021-05-25	criteria provided, single submitter	clinical testing	Functional studies using transgenic mouse models showed mouse erythrocytes with this variant sickled upon deoxygenation (Greaves et al., 1990) and kinetic studies indicate this variant drastically decreases the molecular stability of the protein (Adachi et al., 1987); Commonly referred to as p.(E6V) due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 20825310, 1802884, 30315176, 3267215, 24123366, 20954261, 22975760, 23065522, 22625666, 19465909, 20305663, 20981092, 22010933, 22028795, 22957039, 23144702, 2296310, 27884173, 27254408, 17393956, 28356267, 26372199, 19758965, 12124399, 22244832, 20861612, 30655275, 30290004, 21329186, 15543018, 30033078, 31553106, 31130284, 31980526, 27650483, 32817264, 32371413, 25023084, 2888754, 31589614, 25087612)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000016574	SCV000584093	pathogenic	Hb SS disease	2018-04-16	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224000	SCV000603887	pathogenic	not provided	2023-11-29	criteria provided, single submitter	clinical testing	The Hb S variant (HBB: c.20A>T; p.Glu7Val, also known as Glu6Val when numbered from the mature protein, HbVar ID: 226, rs334) is a common pathogenic beta globin variant. Heterozygosity for Hb S is consistent with sickle cell trait. Homozygosity for Hb S results in sickle cell anemia. Hb S in combination with a different pathogenic HBB variant on the opposite chromosome results in various forms of sickle cell disease (see HbVar link and references therein). References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html
Ambry Genetics	RCV000623118	SCV000741189	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Illumina Laboratory Services, Illumina	RCV000016574	SCV000914520	pathogenic	Hb SS disease	2023-05-06	criteria provided, single submitter	clinical testing	The HBB c.20A>T (p.Glu7Val) missense variant, also referred to as p.Glu6Val, has been reported in a homozygous state in more than 1000 individuals with sickle cell anemia (PMID: 25023084; 25023085; 26275168). The highest frequency of this allele in the Genome Aggregation Database is 0.04490 in the African/African-American population (version 2.1.1). This frequency is high, however, carriers are hypothesized to confer protection against Plasmodium falciparum malaria infection (PMID: 21045822). In mice expressing the sickle trait variant, erythrocytes were shown to sickle with deoxygenation, similar to that seen in humans with sickle cell anemia (PMID: 2296310), and in mice with 100% expression of the sickle cell variant, chronic hemolytic anemia with circulating sickled erythrocytes, as well as chronic tissue damage, was observed (PMID: 12124399). Based on the available evidence, the c.20A>T (p.Glu7Val) variant is classified as pathogenic for sickle cell disease.
Invitae	RCV000224000	SCV000949988	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 7 of the HBB protein (p.Glu7Val). This variant is present in population databases (rs334, gnomAD 5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with sickle cell disease (PMID: 19758965, 20301551, 20861612, 26372199). This variant is also known as p.Glu6Val and HbS. ClinVar contains an entry for this variant (Variation ID: 15333). 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: 1802884, 12124399, 28356267). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000016574	SCV000967671	pathogenic	Hb SS disease	2017-04-25	criteria provided, single submitter	clinical testing	The p.Glu7Val variant (also known as Glu6Val and hemoglobin S variant) in HBB ha s been identified in 1088/24028 (4.5%) of African chromosomes by the Genome Aggr egation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs77121243). T he p.Glu7Val variant in HBB, in the homozygous state, causes sickle cell anemia, which accounts for 60-70% of sickle cell disease in the US. Co-inheritance with a second HBB variant associated with abnormal hemoglobin (such as Hb C, Hb D, H b O, Hb E and ?-thalassemia pathogenic variants) results in sickle cell disease.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000016574	SCV000996163	pathogenic	Hb SS disease	2018-06-29	criteria provided, single submitter	clinical testing	The c.20A>T (p.Glu7Val) variant in HBB (also known as p.Glu6Val) is the most prevalent genotype associated with sickle cell disease (PMID: 25203083). This variant is an established disease-associated mutation and has been reported as pathogenic by multiple clinical diagnostic laboratories in ClinVar (variant ID: 15333). Based on the available evidence, the c.20A>T (p.Glu7Val) variant is classified as pathogenic.
Mendelics	RCV000576548	SCV001138222	pathogenic	beta Thalassemia	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000016574	SCV001163295	pathogenic	Hb SS disease	2021-04-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576548	SCV001194011	pathogenic	beta Thalassemia	2019-10-18	criteria provided, single submitter	clinical testing	NM_000518.4(HBB):c.20A>T(E7V, aka Hb S) is classified as pathogenic and is associated with hemoglobin S (sickle cell disease). Sources cited for classification include the following: PMID 19061217, 2582106, 22028795, 22625666, 22010933, 2888754, 20954261, 6583683, 1376298. Classification of NM_000518.4(HBB):c.20A>T(E7V, aka Hb S) 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.‚Äã
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192494	SCV001360653	pathogenic	Sickle cell disease and related diseases	2019-10-14	criteria provided, single submitter	clinical testing	Variant summary: HBB c.20A>T (p.Glu7Val) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0035 in 251180 control chromosomes in the gnomAD database, including 3 homozygotes. c.20A>T has been reported in the literature in multiple individuals affected with Sickle Cell Disease, an inherited monogenic disease characterized by intravascular sickling, haemolysis, anemia and leukocytosis as well as the association between sickled red blood cells and other blood components (example, Domingos_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in decreased solubility of deoxygenated Hb S, and polymerization which leads to the formation of an extensive network of fibers in red blood cells (example, Adachi_1991). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000016574	SCV001423600	pathogenic	Hb SS disease	2018-05-09	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS3, PM3, PM5, PS4_Moderate, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is detected in trans with a known pathogenic variant [PM3], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000224000	SCV001450316	pathogenic	not provided	2016-03-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000224000	SCV001714970	pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001535873	SCV001752492	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
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000016574	SCV001984022	pathogenic	Hb SS disease	2021-03-10	criteria provided, single submitter	clinical testing
H3Africa Consortium	RCV000016574	SCV002014636	pathogenic	Hb SS disease	2022-10-12	criteria provided, single submitter	research	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.53, its frequency in African populations is >5%, as there is a high prevalence of sickle cell disease in African ancestry individuals.
Revvity Omics, Revvity	RCV000224000	SCV002024975	pathogenic	not provided	2023-10-29	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000016574	SCV002028318	pathogenic	Hb SS disease	2021-09-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000016574	SCV002030204	pathogenic	Hb SS disease	2022-01-11	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
3billion	RCV000016574	SCV002058326	pathogenic	Hb SS disease	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015333, PMID:3267215, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 25023084, 25203083, 25023085, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 1802884, 2296310, 28356267, 12124399, PS3_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23591685, 29542687, PM3_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015126,VCV000036301, PMID:19460936,6129204,8294201, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.83, PP3_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV000224000	SCV002062958	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	HBB: PM3:Very Strong, PM2, PP4, BP4
Genomics Facility, Ludwig-Maximilians-Universität München	RCV000016574	SCV002073896	pathogenic	Hb SS disease	2021-12-28	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000016574	SCV002097812	pathogenic	Hb SS disease	2021-02-10	criteria provided, single submitter	clinical testing	The c.20A>T (p.Glu7Val) variant in HBB (also known as p.Glu6Val) is the most prevalent genotype associated with sickle cell disease [PMID: 25203083]. This variant is an established disease-associated mutation and has been reported as pathogenic by multiple clinical diagnostic laboratories in ClinVar (variant ID: 15333). This variant is identified in gnomAD in 1826 heterozygous individuals, 9 homozygous individuals, with an allele frequency of 1.27e-2. Based on the available evidence, the c.20A>T (p.Glu7Val) variant is classified as pathogenic.
DASA	RCV001824571	SCV002107097	pathogenic	HBB-Related Disorders	2022-03-05	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 13464827; 11880644; 11830454; 12124399; 28356267; 1802884) - PS3.The c.20A>T;p.(Glu7Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 15333; PMID: 20301551; PMID: 30002798; PMID: 15658184;PMID: 7384810; PMID: 6268660; PMID: 26372199; PMID: 26275168; PMID: 28356267; PMID: 22625666; PMID: 32527859) - PS4. The p.(Glu7Val) was detected in trans with a pathogenic variant (PMID: 15658184; PMID: 20861612; PMID: 21131035) - PM3_very strong. Pathogenic missense variant in this residue have been reported (ClinVar ID: 15126 PMID: 20301551; 27117572; 26372199) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 21302591; 34334128; 14084634; 26041415) - PP1_strong.and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000224000	SCV002502707	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251908	SCV002522968	pathogenic	See cases	2022-01-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM3, BS1
Genetics and Molecular Pathology, SA Pathology	RCV002288496	SCV002556466	pathogenic	Beta-thalassemia HBB/LCRB	2019-09-06	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000016574	SCV002556497	pathogenic	Hb SS disease	2020-02-06	criteria provided, single submitter	clinical testing	PS4, PS3, PP1, PP5, PP4.
MGZ Medical Genetics Center	RCV002288496	SCV002581124	pathogenic	Beta-thalassemia HBB/LCRB	2022-07-22	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000016574	SCV002583820	pathogenic	Hb SS disease	2022-08-10	criteria provided, single submitter	clinical testing	PS3, PS4, PM3, PP1
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000576548	SCV002767565	pathogenic	beta Thalassemia	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_000518.5(HBB):c.20A>T, has been identified in exon 1 of 3 of the HBB gene. The variant is predicted to result in a major amino acid change from glutamic acid to valine at position 7 of the protein (NP_000509.1(HBB):p.(Glu7Val)). The glutamic acid at this position has low conservation (100 vertebrates, UCSC), and is located within the Hb-beta like functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.4% (1228 heterozygous, 4 homozygous). An alternative residue change has been reported in the gnomAD database at a frequency of 0.1%. The variant is the cause of hemoglobin S which results in sickle cell anemia and has been previously described as pathogenic and segregated with disease in multiple families (ClinVar; Kwiatkowski, D.P. 2005). Even though often fatal when homozygous or compound heterozygous, it is seen in high frequency (~10%) in populations in Sub-Saharan African and Middle East where it has been positively selected because it confers protection against malaria in heterozygous individuals, which are asymptomatic (Kwiatkowski, D.P. 2005). Additionally, functional studies showed that erythrocytes from transgenic mice expressing human HBB sickle readily on deoxygenation (Greaves, D.R. et al., 1990). A different variant in the same codon resulting in a change to lysine has been reported to cause a mild hemolytic anemia (ClinVar; Kwiatkowski, D.P. 2005). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Johns Hopkins Genomics, Johns Hopkins University	RCV003150808	SCV003839051	pathogenic	Sickle cell-hemoglobin C disease	2023-02-17	criteria provided, single submitter	clinical testing	This HBB variant (rs334) reaches polymorphic frequency (>1%) within the African/African American subpopulation in a large population dataset (gnomAD: 1121/24964 total alleles; 4.49%; 4 homozygotes) and has been reported in ClinVar. It is the most common pathogenic HBB variant in individuals of African ancestry. Also known as p.Glu6Val and HbS, it has been reported in a homozygous or compound heterozygous state in individuals with beta-hemoglobinopathies. One bioinformatic tool queried predicts that this substitution would damaging, while another predicts it would be tolerated. 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.20A>T (p.Glu7Val) to be pathogenic.
Lifecell International Pvt. Ltd	RCV000016574	SCV003845197	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.20A>T in Exon 1 of the HBB gene that results in the amino acid substitution p.Glu7Val was identified. The observed variant has a minor allele frequency of 0.00348% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic, Likely Benign, and Conflicting Interpretations (Variant ID: 15333). This variant has previously been reported for sickle cell anemia by Jaripour ME, et, al., 2018. Experimental studies have shown that this missense change affects HBB function by Eshbach ML, et, al, 2017. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001824571	SCV004046417	pathogenic	HBB-Related Disorders		criteria provided, single submitter	clinical testing	The c.20A>T (p.Glu7Val) variant in HBB, also known as p.Glu6Val, is referred to as the hemoglobin S allele (HbS) and causes autosomal recessive sickle cell disease (MIM: #603903) when it is homozygous or compound heterozygous with a different pathogenic variant. Individuals who are heterozygous for the HbS allele have sickle cell trait (SCT). The c.20A>T (p.Glu7Val) variant is the most prevalent genotype associated with sickle cell disease (PMID: 25203083). This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. It is present at a frequency of 0.4% (1236/282580 heterozygotes and 4/282580 homozygotes) in the gnomAD population database. The c.20A>T (p.Glu7Val) variant is an established disease-causing mutation. Based on the available evidence, c.20A>T(p.Glu7Val) is classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000016574	SCV004048527	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing	The missense c.20A>T (p.Glu7Val) variant in HBB has been reported in homozygous individuals affected with sickle cell anemia and heterozygous state in sickle cell anemia trait. This is a common, well-known variant that has been observed in individuals affected with sickle cell disease (Kutlar, Ferdane et al.,2010 and Bender, MA.,2003). Experimental studies have shown that this missense change affects hemoglobin polymerization and can result in abnormally-shaped red blood cells (He, Zhenning et al.,2002, Eshbach, Megan L et al.,2017). This variant is reported with the allele frequency 0.4% in the gnomAD and 2.7% in 1000 genome database. It has been submitted to ClinVar as Pathogenic. The amino acid Glu at position 7 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Glu7Val in HBB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003407340	SCV004113642	pathogenic	HBB-related condition	2024-01-14	criteria provided, single submitter	clinical testing	The HBB c.20A>T variant is predicted to result in the amino acid substitution p.Glu7Val. This variant, also referred to as p.Glu6Val using legacy nomenclature, has previously been reported to be causative for sickle cell anemia when present in the homozygous state (Engelke et al. 1988. PubMed ID: 3267215; Bender et al. 2017. PubMed ID: 20301551). Individuals heterozygous for this variant have sickle cell trait and are usually asymptomatic but can be at risk for complications (Key and Derebail. 2010. PubMed ID: 21239829). This variant is reported in 4.5% of alleles in individuals of African descent in gnomAD. We interpret this variant as pathogenic.
OMIM	RCV000016573	SCV000036842	other	HEMOGLOBIN S	2019-11-14	no assertion criteria provided	literature only
OMIM	RCV000016574	SCV000036843	pathogenic	Hb SS disease	2019-11-14	no assertion criteria provided	literature only
OMIM	RCV000016575	SCV000036844	protective	Malaria, resistance to	2011-12-02	no assertion criteria provided	literature only
GeneReviews	RCV000016574	SCV000190688	not provided	Hb SS disease		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477892	SCV000536833	pathogenic	Dominant beta-thalassemia; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; Malaria, susceptibility to; beta Thalassemia	2016-02-23	no assertion criteria provided	research
Gharavi Laboratory, Columbia University	RCV000224000	SCV000809296	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000723337	SCV000854734	pathogenic	Fetal hemoglobin quantitative trait locus 1	2018-07-19	no assertion criteria provided	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000576548	SCV001142414	pathogenic	beta Thalassemia	2020-01-06	no assertion criteria provided	curation	NM_000518.4:c.20A>T is also known as p.Glu6Lys or HbS in the literature. NM_000518.4:c.20A>T in the HBB gene has an allele frequency of 0.045 in African subpopulation in the gnomAD database. The c.20A>T (p.Glu7Val) variant in HBB is the most prevalent genotype associated with sickle cell disease (PMID: 25203083). Kondani et al reported that among 247 children, 19 (7.7%) were homozygous sickle cell anemia patients (Hb SS) (PMID: 25023084). Experimental studies have shown that this missense change affects hemoglobin polymerization and can result in abnormally-shaped red blood cells (PMID: 12124399; 28356267; 1802884). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PS3; PM3; PP4.
New York Genome Center	RCV001255121	SCV001431215	pathogenic	Anemia	2020-01-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224000	SCV001743401	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000224000	SCV001932948	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224000	SCV001955042	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224000	SCV001975550	pathogenic	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000016574	SCV002064353	pathogenic	Hb SS disease	2022-01-07	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001824571	SCV002075077	not provided	HBB-Related Disorders		no assertion provided	phenotyping only	Variant identified in multiple registry participants. Variant interpreted as consistent with alpha thalassemia trait and reported on 02-28-2020 by Lab or GTR ID 500068. Variant interpreted as Pathogenic and reported on 07-21-2020 by Lab or GTR ID 1197. Variant interpreted as Pathogenic and reported on 05-26-2021 by Lab or GTR ID 20290. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000576548	SCV002091614	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000576548	SCV003931163	not provided	beta Thalassemia		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 02-03-2017 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000016574	SCV004024078	pathogenic	Hb SS disease		no assertion criteria provided	research