NM_000518.4(HBB):c.410G>A (p.Gly137Asp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 25, 2023
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:: RCV001284489.21

Allele description [Variation Report for NM_000518.4(HBB):c.410G>A (p.Gly137Asp)]

NM_000518.4(HBB):c.410G>A (p.Gly137Asp)

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_000518.4(HBB):c.410G>A (p.Gly137Asp)

Other names:

G136D; Hb Hope

HGVS:

NC_000011.10:g.5225632C>T
NG_000007.3:g.71984G>A
NG_046672.1:g.3567C>T
NG_053049.1:g.1953C>T
NG_059281.1:g.6440G>A
NM_000518.5:c.410G>AMANE SELECT
NP_000509.1:p.Gly137Asp
NP_000509.1:p.Gly137Asp
LRG_1232t1:c.410G>A
HBB:c.410G>A
LRG_1232:g.6440G>A
LRG_1232p1:p.Gly137Asp
NC_000011.9:g.5246862C>T
NM_000518.3:c.410G>A
NM_000518.4:c.410G>A
P68871:p.Gly137Asp

Protein change:

G137D; GLY136ASP

Links:

HBVAR: 548; UniProtKB: P68871#VAR_003075; OMIM: 141900.0112; dbSNP: rs33949486

NCBI 1000 Genomes Browser:

rs33949486

Molecular consequence:

NM_000518.5:c.410G>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
SCV000603900	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely benign (Apr 24, 2023)	germline	clinical testing	Citation Link,
SCV001470316	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jul 25, 2023)	unknown	clinical testing	PubMed (26) [See all records that cite these PMIDs] 35023007, 31164695, 31240559, 31553106, 6500990, 808079, 26351951, 28125089, 25244406, 1428947, 1634366, 22145566, 14282052, 932531, 429843, 29464999, 31106603, 33244864, 33287582, 23297836, 19429541, 15658184, 26524961, 27207683, 25130136, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000603900

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Likely benign
(Apr 24, 2023)

germline

clinical testing

Citation Link,

SCV001470316

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jul 25, 2023)

unknown

clinical testing

PubMed (26)
[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	unknown	unknown	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

Spectrum of HBB gene mutations among 696 β-thalassemia patients and carriers in Southern Vietnam.

Xinh PT, Chuong HQ, Ha NTT, Tram HDB, Van Dong C, Thanh LVH, Hoa NTH, Nghia H, Binh NT, Dung PC, Vu HA.

Mol Biol Rep. 2022 Apr;49(4):2601-2606. doi: 10.1007/s11033-021-07062-w. Epub 2022 Jan 13.

PubMed [citation]

PMID:: 35023007

Molecular epidemiology, pathogenicity, and structural analysis of haemoglobin variants in the Yunnan province population of Southwestern China.

Zhang J, Li P, Yang Y, Yan Y, Zeng X, Li D, Chen H, Su J, Zhu B.

Sci Rep. 2019 Jun 4;9(1):8264. doi: 10.1038/s41598-019-44793-0.

PubMed [citation]

PMID:: 31164695
PMCID:: PMC6547717

See all PubMed Citations (26)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603900.8

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

#	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, SCV001470316.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (26)

Description

The HBB c.410G>A (p.Gly137Asp) variant has been reported in the published literature in heterozygous individuals appearing normal without clinical or hematological abnormalities, including those also carrying Hb E and Hb C (PMIDs: 14282052 (1965), 1634366 (1992), 23297836 (2013), and 25244406 (2014)). However, some compound heterozygous patients that carry either Hb S or Hb Grady present with mild hemolytic anemia (PMID: 6500990 (1984) and 26351951 (2016)). This variant has also been seen in patients affected with deletional alpha thalassemia intermedia (PMID: 22145566 (2012)). Functional studies indicate that this variant is mildly unstable, has decreased oxygen affinity, and diminished cooperativity (PMID: 932531 (1976)). The frequency of this variant in the general population, 0.00018 (3/16256 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 predictions that this variant is damaging. 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

Last Updated: Oct 26, 2024

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