NM_000518.5(HBB):c.328G>A (p.Val110Met) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 6, 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:: RCV003476897.2

Allele description [Variation Report for NM_000518.5(HBB):c.328G>A (p.Val110Met)]

NM_000518.5(HBB):c.328G>A (p.Val110Met)

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.328G>A (p.Val110Met)

Other names:

V109M

HGVS:

NC_000011.10:g.5225714C>T
NG_000007.3:g.71902G>A
NG_046672.1:g.3649C>T
NG_053049.1:g.2035C>T
NG_059281.1:g.6358G>A
NM_000518.5:c.328G>AMANE SELECT
NP_000509.1:p.Val110Met
LRG_1232t1:c.328G>A
LRG_1232:g.6358G>A
LRG_1232p1:p.Val110Met
NC_000011.9:g.5246944C>T
NM_000518.4:c.328G>A
P68871:p.Val110Met

Protein change:

V110M; VAL109MET

Links:

UniProtKB: P68871#VAR_003032; OMIM: 141900.0252; dbSNP: rs33969677

NCBI 1000 Genomes Browser:

rs33969677

Molecular consequence:

NM_000518.5:c.328G>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
SCV000885556	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Mar 6, 2023)	germline	clinical testing	Citation Link,
SCV004219882	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Sep 26, 2022)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 6863429, 1201208, 7615400, 31304856, 30423154, 27651169, 23859443, 18818920, 18793248, 8144354, 3957694, 7204093, 24200101, 4808644, 4808645, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000885556

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Pathogenic
(Mar 6, 2023)

germline

clinical testing

Citation Link,

SCV004219882

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Sep 26, 2022)

unknown

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

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

Identification and quantitation of Hb Olympia [beta 20(B2)Val leads to Met] and Hb San Diego [beta 109(G11)Val leads to Met] by high-performance liquid chromatography.

Nakatsuji I, Wilson JB, Lam H, Huisman TH.

J Chromatogr. 1983 Apr 15;259(3):511-4. No abstract available.

PubMed [citation]

PMID:: 6863429

Erythraemia due to haemoglobin San Diego.

Chanarin I, Samson D, Lang A, Casey R, Lorkin PA, Lehmann H.

Br J Haematol. 1975 Jun;30(2):167-75.

PubMed [citation]

PMID:: 1201208

See all PubMed Citations (16)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885556.3

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

Description

The Hb San Diego variant (HBB: c.328G>A; p.Val110Met, also known as Val109Met when numbered from the mature protein, rs33969677) has been reported in a heterozygous state in multiple individuals with familial erythrocytosis (Bento 2013, Gonzalez Fernandez 2009, Nute 1974, HbVar database and references therein). It is listed in ClinVar (Variation ID: 15342), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The residue Val110 is within the alpha1beta2 contact zone, which is important for oxygen uptake and its related allosteric effects (Gonzalez Fernandez 2009). The valine at codon 110 is moderately conserved, and functional characterization of the variant hemoglobin demonstrates increased oxygen affinity (reduced P50), resulting in reduced oxygen release to the tissue (Chanarin 1975, Nute 1974). In addition, this variant has been shown to segregate with increased oxygen affinity (Nute 1974). An additional high oxygen affinity Hb variant at this position (Hb Johnstown: Val110Leu) has also been described in association with erythrocytosis (Feliu-Torres 2004). Based on available information, the Hb San Diego variant is considered pathogenic for familial erythrocytosis. REFERENCES Link to HbVar database for Hb San Diego: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=483 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; 91(4):361-8. Chanarin I et al. Erythraemia due to haemoglobin San Diego. Br J Haematol. 1975; 30(2):167-75. Feliu-Torres A et al. Hb Johnstown (beta109(G11)Val-->Leu): A high oxygen affinity variant associated with beta0-thalassemia. Hemoglobin. 2004;28(4):335-8. Gonzalez Fernandez F et al. Haemoglobinopathies with high oxygen affinity. Experience of Erythropathology Cooperative Spanish Group. Ann Hematol. 2009; 88(3):235-8. Nute P et al. Hemoglobinopathic erythrocytosis due to a new electrophoretically silent variant, hemoglobin San Diego (beta109 (G11)val--met). J Clin Invest. 1974;53(1):320-8.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219882.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals and families affected with erythrocytosis (PMIDs: 1201208 (1975), 7204093 (1981), 6863429 (1983), 18818920 (2009), 23859443 (2013), and 27651169 (2016). This variant has also been shown to co-segregate with erythrocytosis (PMIDs: 18793248 (2009), 30423154 (2019), and 31304856 (2019)). This variant has also been shown to co-segregate with erythrocytosis (PMIDs: 18793248 (2009) and 30423154 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. 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

Last Updated: Nov 3, 2024

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