NM_000518.5(HBB):c.61G>A (p.Val21Met) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 1, 2023
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:: RCV000759801.18

Allele description [Variation Report for NM_000518.5(HBB):c.61G>A (p.Val21Met)]

NM_000518.5(HBB):c.61G>A (p.Val21Met)

Genes:

LOC106099062:HBB recombination 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.61G>A (p.Val21Met)

Other names:

V20M

HGVS:

NC_000011.10:g.5226961C>T
NG_000007.3:g.70655G>A
NG_042296.1:g.492C>T
NG_046672.1:g.4896C>T
NG_059281.1:g.5111G>A
NM_000518.5:c.61G>AMANE SELECT
NP_000509.1:p.Val21Met
LRG_1232t1:c.61G>A
LRG_1232:g.5111G>A
LRG_1232p1:p.Val21Met
NC_000011.9:g.5248191C>T
NM_000518.4:c.61G>A
P68871:p.Val21Met

Protein change:

V21M; VAL20MET

Links:

UniProtKB: P68871#VAR_002889; OMIM: 141900.0210; dbSNP: rs35890959

NCBI 1000 Genomes Browser:

rs35890959

Molecular consequence:

NM_000518.5:c.61G>A - 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
SCV000889375	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jun 22, 2018)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 35052472, 31553106, 18818920, 23859443, 19429541, 2599884, 20642336, 26467025
SCV001474509	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Mar 4, 2020)	germline	clinical testing	Citation Link,
SCV005201873	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Dec 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000889375

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Jun 22, 2018)

unknown

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001474509

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Mar 4, 2020)

germline

clinical testing

Citation Link,

SCV005201873

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Dec 1, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Importance of Sequencing HBA1, HBA2 and HBB Genes to Confirm the Diagnosis of High Oxygen Affinity Hemoglobin.

Filser M, Gardie B, Wemeau M, Aguilar-Martinez P, Giansily-Blaizot M, Girodon F.

Genes (Basel). 2022 Jan 12;13(1). doi: 10.3390/genes13010132.

PubMed [citation]

PMID:: 35052472
PMCID:: PMC8774638

Curating the gnomAD database: Report of novel variants in the globin-coding genes and bioinformatics analysis.

Scheps KG, Hasenahuer MA, Parisi G, Targovnik HM, Fornasari MS.

Hum Mutat. 2020 Jan;41(1):81-102. doi: 10.1002/humu.23925. Epub 2019 Oct 14.

PubMed [citation]

PMID:: 31553106

See all PubMed Citations (8)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889375.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The HBB c.61G>A (p.Val21Met) variant, also known as Hb Olympia has been reported in individuals presenting with erythrocytosis (PMIDs: 35052427 (2022), 23859443 (2013), and 2599884 (1989)). In addition, this variant has been reported to have increased oxygen affinity and is mildly unstable (PMIDs: 31553106 (2020) and 2599884 (1989)). Based on the available information, this variant is classified as pathogenic.

#	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, SCV001474509.1

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

Description

The Hb Olympia variant (HBB: c.61G>A; p.Val21Met, also known as Val20Met when numbered from the mature protein, rs35890959) is reported in the literature in multiple individuals affected with erythrocytosis (Bento 2013, Gonzalez Fernandez 2009, Percy 2009, Stamatoyannopoulos 1973, Wajcman 2005, HbVar database and references therein). This variant has been observed to segregate with erythrocytosis in a family in a pattern consistent with autosomal dominant inheritance (Stamatoyannopoulos 1973). Further, while heterozygous individuals with this variant are reported with mild erythrocytosis, those carrying both Hb Olympia and a beta-thalassemia allele are reported to exhibit more severe symptoms (Wajcman 2005). The Hb Olympia variant is found on a single chromosome in the Genome Aggregation Database (1/251260 alleles), indicating it is not a common polymorphism. The valine at codon 21 is highly conserved, and functional studies indicate increased oxygen affinity of the variant protein (Stamatoyannopoulos 1973). Based on available information, this variant is considered to be pathogenic. References: HbVar link to Hb Olympia: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=257 Bento C et al. Molecular study of congenital erythrocytosis in 70 unrelated patients revealed a potential causal mutation in less than half of the cases (Where is/are the missing gene(s)?). Eur J Haematol. 2013 Oct;91(4):361-8. Gonzalez Fernandez FA et al. Haemoglobinopathies with high oxygen affinity. Experience of Erythropathology Cooperative Spanish Group. Ann Hematol. 2009 Mar;88(3):235-8. Percy MJ et al. Identification of high oxygen affinity hemoglobin variants in the investigation of patients with erythrocytosis. Haematologica. 2009 Sep;94(9):1321-2. Stamatoyannopoulos G et al. Hemoglobin olympia ( 20 valine leads to methionine): an electrophoretically silent variant associated with high oxygen affinity and erythrocytosis. J Clin Invest. 1973 Feb;52(2):342-9. 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

From GeneDx, SCV005201873.1

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18818920, 2599884, 4683875, 6745619, 19429541, 23859443, 31553106, 35052472, 8891722, 20642336, 6863429, 15921161)

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

Last Updated: Nov 24, 2024

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