NM_000518.5(HBB):c.437A>G (p.Tyr146Cys) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 21, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001284491.14

Allele description [Variation Report for NM_000518.5(HBB):c.437A>G (p.Tyr146Cys)]

NM_000518.5(HBB):c.437A>G (p.Tyr146Cys)

Genes:

LOC110006319:beta-globin gene 3' regulatory region [Gene]
HBB:hemoglobin subunit beta [Gene - OMIM - HGNC]
LOC107133510:origin of replication at HBB [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000518.5(HBB):c.437A>G (p.Tyr146Cys)

Other names:

Y145C

HGVS:

NC_000011.10:g.5225605T>C
NG_000007.3:g.72011A>G
NG_046672.1:g.3540T>C
NG_053049.1:g.1926T>C
NG_059281.1:g.6467A>G
NM_000518.5:c.437A>GMANE SELECT
NP_000509.1:p.Tyr146Cys
LRG_1232t1:c.437A>G
LRG_1232:g.6467A>G
LRG_1232p1:p.Tyr146Cys
NC_000011.9:g.5246835T>C
NM_000518.4:c.437A>G
P68871:p.Tyr146Cys

Protein change:

Y146C; TYR145CYS

Links:

UniProtKB: P68871#VAR_003090; OMIM: 141900.0232; dbSNP: rs35117167

NCBI 1000 Genomes Browser:

rs35117167

Molecular consequence:

NM_000518.5:c.437A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001470318	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Nov 11, 2019)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 747183, 5796352, 478981, 3793825, 10335979, 28685465, 11946541, 8954892, 29790589, 31132167, 26467025
SCV001474477	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Apr 21, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001470318

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Nov 11, 2019)

unknown

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV001474477

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Apr 21, 2020)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Myelofibrosis with complex chromosome abnormality in a patient with erythrocytosis due to hemoglobin Rainier and treated with 32P.

Najfeld V, Price TH, Adamson JW, Fialkow PJ.

Am J Hematol. 1978;5(1):63-9.

PubMed [citation]

PMID:: 747183

Erythrocytosis associated with hemoglobin Rainier: oxygen equilibria and marrow regulation.

Adamson JW, Parer JT, Stamatoyannopoulos G.

J Clin Invest. 1969 Aug;48(8):1376-86.

PubMed [citation]

PMID:: 5796352
PMCID:: PMC322364

See all PubMed Citations (11)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001470318.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Not found in the total gnomAD dataset, and the data is high quality. Conflicting predictions of the effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001474477.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The Hb Rainier variant (HBB: c.437A>G; p.Tyr146Cys, also known as Tyr145Cys when numbered from the mature protein, rs35117167) is reported in the literature in the heterozygous state in multiple individuals affected with erythrocytosis (see link to HbVar and references therein, Adamson 1969). This variant is reported in ClinVar (Variation ID: 15322), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 146 is highly conserved, and functional analyses of the variant protein show increased oxygen affinity (see link to HbVar, Adamson 1969). Additionally, other amino acid substitutions at this codon (Hb Nancy, Hb Osler, Hb Bethesda, Hb McKees Rocks) have been reported in individuals with erythrocytosis and are considered pathogenic (HbVar IDs: 570, 572, 573, 574), and several hemoglobin variants with high oxygen affinity leading to erythrocytosis are located at the carboxy-terminal end of the HBB gene (Wajcman 2004). Based on available information, the Hb Rainier variant is considered to be pathogenic. References: Link to HbVar for Hb Rainier: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=571 Adamson JW et al. Erythrocytosis associated with hemoglobin Rainier: oxygen equilibria and marrow regulation. J Clin Invest. 1969 Aug;48(8):1376-86. Wajcman H and Galacteros F. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin. 2005;29(2):91-106.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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