NM_000518.4(HBB):c.208G>A (p.Gly70Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Jan 30, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000587680.25

Allele description [Variation Report for NM_000518.4(HBB):c.208G>A (p.Gly70Ser)]

NM_000518.4(HBB):c.208G>A (p.Gly70Ser)

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_000518.4(HBB):c.208G>A (p.Gly70Ser)

Other names:

G69S; Hb City of Hope

HGVS:

NC_000011.10:g.5226684C>T
NG_000007.3:g.70932G>A
NG_042296.1:g.215C>T
NG_046672.1:g.4619C>T
NG_053049.1:g.3005C>T
NG_059281.1:g.5388G>A
NM_000518.5:c.208G>AMANE SELECT
NP_000509.1:p.Gly70Ser
LRG_1232t1:c.208G>A
LRG_1232:g.5388G>A
LRG_1232p1:p.Gly70Ser
NC_000011.9:g.5247914C>T
NM_000518.4:c.208G>A
P68871:p.Gly70Ser

Protein change:

G70S; GLY69SER

Links:

HBVAR: 377; UniProtKB: P68871#VAR_002968; OMIM: 141900.0050; dbSNP: rs33947415

NCBI 1000 Genomes Browser:

rs33947415

Molecular consequence:

NM_000518.5:c.208G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

unknown functional consequence

Observations:

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
SCV000333005	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Aug 8, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000941382	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 2200760, 2467892, 25113778, 28492532
SCV001470522	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jun 1, 2023)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 34426522, 21302591, 25113778, 27207683, 27823958, 31268351, 28802248, 6434492, 31553106, 1353069, 26436569, 34092029, 2467892, 26467025
SCV002013116	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 7, 2023)	germline	clinical testing	Citation Link,
SCV002023455	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004564623	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Jan 23, 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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	7	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

Beta-thalassemia in Turkey.

Oner R, Altay C, Gurgey A, Aksoy M, Kilinç Y, Stoming TA, Reese AL, Kutlar A, Kutlar F, Huisman TH.

Hemoglobin. 1990;14(1):1-13. Review.

PubMed [citation]

PMID:: 2200760

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (17)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000333005.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (1)

#	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		7	not provided	not provided	not provided

From Invitae, SCV000941382.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 70 of the HBB protein (p.Gly70Ser). This variant is present in population databases (rs33947415, gnomAD 1.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive mild to moderate beta thalassemia phenotypes and/or severe anemia and immunodeficiency (PMID: 2200760, 2467892, 25113778). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly69Ser, G69S, Hb City of Hope, and Hb CH. ClinVar contains an entry for this variant (Variation ID: 15138). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HBB protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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, SCV001470522.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

The HBB c.208G>A (p.Gly70Ser) variant (also known as Hb City of Hope) has been reported as having normal stability, with normal clinical presentation in heterozygotes (PMID: 6434492 (1984)). However, compound heterozygous individuals carrying this variant and a severe beta-thalassemia variant on the other allele may present with a beta-thalassemia intermedia phenotype (PMIDs: 25113778 (2015), 2467892 (1989)). The frequency of this variant in the general population, 0.018 (184/10366 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant.

#	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 GeneDx, SCV002013116.3

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

Description

Also known as Hb City of Hope (HbCH) and G69S using alternate nomenclature; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31553106, 34297361, 28802248, 27823958, 31268351, 21302591, 25113778, 1353069, 6434492, 2467892, 34426522)

#	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

From Revvity Omics, Revvity, SCV002023455.3

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

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004564623.1

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

Description

The Hb City of Hope variant (HBB: c.208G>A; p.Gly70Ser, also known as Gly69Ser when numbered from the mature protein; rs33947415, HbVar ID: 377) is reported in the literature in the heterozygous state in asymptomatic individuals (HbVar and references therein), and in trans to a pathogenic variant in an individual presenting with classical beta-thalassemia trait; however, this individual also carried an alpha-thalassemia deletion (--SEA), which could reduce the globin chain imbalance and minimize the clinical impact (Zhou 2019). Hb City of Hope has also been observed in trans to pathogenic HBB variants in several individuals with thalassemia intermedia or moderate to severe anemia (Paridisi 2010, Vinciguerra 2015). This variant is reported in ClinVar (Variation ID: 15138). It is found in the Ashkenazi Jewish population with an overall allele frequency of 1.8% (184/10366 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.584). Due to conflicting information, the clinical significance of the Hb City of Hope variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Paradisi I et al. Hemoglobin S/hemoglobin City of Hope compound heterozygote with a SubSaharan genetic background and severe bone marrow hypoplasia. Invest Clin. 2010 Sep;51(3):403-14. PMID: 21302591. Vinciguerra M et al. Co-inheritance of the rare B hemoglobin variants Hb Yaounde, Hb Gorwihl and Hb City of Hope with other alterations in globin genes: impact in genetic counseling. Eur J Haematol. 2015 Apr;94(4):322-9. PMID: 25113778. Zhou JY et al. Coinheritance of Hb City of Hope (HBB: c.208G>A) and B-Thalassemia: Compromising the Molecular Diagnosis of the Codons 71/72 (+A) (HBB: c.216_217insA) Mutation by Reverse Dot-Blot Hybridization. Hemoglobin. 2019 Mar;43(2):145-147. PMID: 31268351.

#	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: May 12, 2024

ClinVar

Relating variation to medicine