rs33985544

Variant names:

• chr11-5226701-T-C
• rs33985544
• NM_000518.5:c.191A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-5226701-T-C
• chr11-5226701-T-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000518.5(HBB):​c.191A>G​(p.His64Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H64P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 7.37
• Publications: 2 publications found

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

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 36 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226702-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 15256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-5226701-T-C is Pathogenic according to our data. Variant chr11-5226701-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15400.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.191A>G	p.His64Arg	missense_variant	Exon 2 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.191A>G	p.His64Arg	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Jan 08, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Zurich variant (HBB: c.191A>G; p.His64Arg, also known as His63Arg when numbered from the mature protein, rs33985544, HbVar ID: 358) has been observed in the heterozygous state in asymptomatic individuals or associated with mild reticulocytosis (see HbVar database and references therein). This variant has been associated with episodes of severe drug-induced hemolytic anemia in patients after administration of oxidative drugs particularly sulfonamides (see HbVar, Aguinaga 1998, Miranda 1994). This variant has been reported as mildly unstable with increased oxygen affinity (Aguinaga 1998). This variant is reported in ClinVar (Variation ID: 15400) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The histidine at codon 64 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.983). Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Aguinaga MP et al. Molecular diagnosis and characterization of Hb Zürich [beta63(E7)His-->Arg]] carriers in a Kentucky family. Hemoglobin. 1998 Sep-Nov;22(5-6):509-15. PMID: 9859934. Miranda SR et al. Identification of Hb Zürich [alpha 2 beta 2(63)(E7)His-->Arg] by DNA analysis in a Brazilian family. Hemoglobin. 1994 Sep;18(4-5):337-41. PMID: 7852089. -

Hemoglobinopathy Pathogenic:1

Jan 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.191A>G (p.His64Arg) results in a non-conservative amino acid change in the encoded protein sequence, altering a conserved residue (HGMD) in which another missense variant (p.His64Tyr) is classified as pathogenic. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251428 control chromosomes (gnomAD). c.191A>G has been reported in the literature in heterozygous individuals affected with hemolytic episodes, which was usually described as following sulfonamide treatment, as well as in healthy relatives (e.g. Huisman_1961, Frick_1962, Rieder_1965, Dickerman_1973, Murata_1982, Miranda_1994, Aguinaga_1998). It was also found in the compound heterozygous state with a pathogenic variant in an individual with a phenotype ressembling beta thalassemia intermedia (Yan_2019). These data indicate that the variant is likely associated with hemoglobinopathy in the heterozygous state which manifests as a drug-induced reaction, and may also be associated with disease in the compound heterozygous state with a beta thalassemia allele. Publications report experimental evidence evaluating an impact on protein function (Zinkham_1980, Aguinaga_1998), finding evidence of protein instability and increased carbon monoxide affinity. The following publications have been ascertained in the context of this evaluation (PMID: 6175783, 13716725, 14314237, 4749206, 13895148, 7852089, 9859934, 7384813, 30900795). ClinVar contains an entry for this variant (Variation ID: 15400). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Other:1

Sep 01, 1998

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;.;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.5	D;.;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.99
MutPred		0.94		Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);
MVP		0.99
MPC		0.25
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		-0.0073	Neutral
Varity_R		0.91
gMVP		0.99
Mutation Taster		=3/97	disease causing

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

Other links and lift over

dbSNP: rs33985544; hg19: chr11-5247931;