11-5226702-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000518.5(HBB):c.190C>T(p.His64Tyr) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H64R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 9.10

Publications

8 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 18 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 chr11-5226701-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15400.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 11-5226702-G-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.190C>T	p.His64Tyr	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 link	c.190C>T	p.His64Tyr	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:2

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 02, 2019

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HBB c.190C>T (p.His64Tyr) results in a conservative amino acid change located in a heme binding site (InterPro) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251426 control chromosomes (gnomAD). The variant (also known as Hb M-Saskatoon) is widely regarded as causing hemoglobin M (HbM) disease, and has been reported in the literature in several affected individuals (e.g. Efremov_1974, Waye_1994, Suryantoro_1995, Kedar_2005, Brunner-Agten_2010, Garcia-Morin_2019). The disorder was observed to be inherited in an autosomal dominant pattern, often occurring as a de novo mutation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

not provided

Pathogenic:2

Aug 21, 2025

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBB c.190C>T (p.His64Tyr) variant (also known as Hb M Saskatoon and H63Y) has been reported in the published literature in individuals/families affected with autosomal dominant methemoglobinemia (PMIDs: 34789072 (2021), 30828177 (2019), 4841979 (1974), 13897827 (1961), 20324533 (1950)) or hemoglobinopathy (PMID: 32830468 (2020)) and has been observed to occur de novo (PMIDs: 19727720 (2010), 15929117 (2005), 7713749 (1994)). Functional studies have reported that this variant is damaging to the natural function of beta globin with increased oxygen affinity, increased auto-oxidation, and reduced stability (PMIDs: 30828177 (2019), 15929117 (2005), 4086306 (1985), 7372598 (1980), 6248489 (1980), 4301455 (1968), 5851873 (1965)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic and is associated with autosomal dominant methemoglobinemia.

Jan 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Hb M-Saskatoon variant (HBB: c.190C>T; p.His64Tyr, also known as His63Tyr when numbered from the mature protein, rs33922873, HbVar ID: 359) is reported in the literature in several individuals with hemoglobin M (HbM) disease (Arbane-Dahmane 1985, Bouatrous 2021, Brunner-Agten 2010, Gottgens 2021, Suryantoro 1995, Waye 1994). HbM disease is an autosomal dominantly inherited congenital form of methemoglobinemia, and pathogenic variants often occur de novo (Bouatrous 2021, Brunner-Agten 2010, Waye 1994). This variant is reported in ClinVar (Variation ID: 15256). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.942). Based on available information, the Hb M-Saskatoon variant is considered to be pathogenic for HbM disease. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Arbane-Dahmane M et al. Hemoglobin M Saskatoon (alpha 2 beta 2 63(E7) His----Tyr) in an Algerian family. Hemoglobin. 1985;9(5):509-11. PMID: 4086306. Bouatrous E et al. First Observation of HbM-Saskatoon at the Origin of Neonatal Cyanosis in a Tunisian Baby. J Pediatr Hematol Oncol. 2021 Nov 1;43(8):e1055-e1058. PMID: 33625083. Brunner-Agten S et al. Compound heterozygosity of Hb Hamilton and de novo mutated HbM Saskatoon. Ann Hematol. 2010 May;89(5):517-8. PMID: 19727720. Gottgens EL et al. Cyanosis, hemolysis, decreased HbA1c and abnormal co-oximetry in a patient with hemoglobin M Saskatoon (HBB:c.190C?>?T p.His64Tyr). Hematology. 2021 Dec;26(1):914-918. PMID: 34789072. Suryantoro P et al. C to T transition at the first nucleotide of codon 63 of the beta-globin gene corresponding to hemoglobin M-Saskatoon in an Indonesian boy. Jpn J Hum Genet. 1995 Jun;40(2):195-201. PMID: 7663000. Waye JS et al. De novo beta-globin gene mutation (beta 63(E7)His-->Tyr) giving rise to Hb M disease in a Newfoundlander. Hemoglobin. 1994 Nov;18(6):441-3. PMID: 7713749.

Inborn genetic diseases

Pathogenic:1

Apr 16, 2019

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HEMOGLOBIN M (RADOM) METHEMOGLOBINEMIA, BETA TYPE

Pathogenic:1

Jun 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

METHEMOGLOBINEMIA, BETA TYPE

Pathogenic:1

Mar 17, 2025

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

HEMOGLOBIN M (SASKATOON)

Other:1

May 10, 2018

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

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T;.;T

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.0

.;D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;H;.;.

PhyloP100

9.1

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.7

D;.;.;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0030

D;.;.;D

Sift4G

Uncertain

0.0050

D;.;.;.

Vest4

0.98

ClinPred

0.99

GERP RS

5.1

PromoterAI

-0.0092

Neutral

(source)

Varity_R

0.84

gMVP

0.99

Mutation Taster

=2/98

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over