NM_000517.4(HBA2):c.142G>C (p.Asp48His) AND alpha Thalassemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 10, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001275680.10

Allele description [Variation Report for NM_000517.4(HBA2):c.142G>C (p.Asp48His)]

NM_000517.4(HBA2):c.142G>C (p.Asp48His)

Genes:

LOC106804612:hemoglobin subunit alpha 2 recombination region [Gene]
HBA2:hemoglobin subunit alpha 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000517.4(HBA2):c.142G>C (p.Asp48His)

Other names:

D47H; Hb L-Ferrara; Hb Michigan-I; Hb Michigan-II; Hb Sealy; Hb Sinai

HGVS:

NC_000016.10:g.173171G>C
NG_000006.1:g.34034G>C
NG_046165.1:g.2910G>C
NG_059186.1:g.1521G>C
NG_059271.1:g.5325G>C
NM_000517.6:c.142G>CMANE SELECT
NP_000508.1:p.Asp48His
LRG_1240t1:c.142G>C
LRG_1225:g.1521G>C
LRG_1240:g.5325G>C
LRG_1240p1:p.Asp48His
NC_000016.9:g.223170G>C
NM_000517.4:c.142G>C
P69905:p.Asp48His

Protein change:

D48H; ASP47HIS

Links:

HBVAR: 65; UniProtKB: P69905#VAR_002765; OMIM: 141850.0012; dbSNP: rs281864834

NCBI 1000 Genomes Browser:

rs281864834

Molecular consequence:

NM_000517.6:c.142G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: alpha Thalassemia
Synonyms:: A-Thalassemia; Alpha thalassemia spectrum
Identifiers:: MONDO: MONDO:0011399; MedGen: C0002312; Orphanet: 846; OMIM: 604131

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001461038	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 16, 2020)	germline	clinical testing
SCV005204955	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 10, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7803274, 20309827, 28160324, 25818820, 5780195, 23741188 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001461038

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Sep 16, 2020)

germline

clinical testing

SCV005204955

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jun 10, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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

Citations

PubMed

The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes.

Molchanova TP, Pobedimskaya DD, Huisman TH.

Br J Haematol. 1994 Oct;88(2):300-6.

PubMed [citation]

PMID:: 7803274

Abnormal hemoglobin phenotypes in carriers of mild anemia in Latin America.

Zamaro PJ, Bonini-Domingos CR.

Genet Mol Res. 2010 Mar 9;9(1):425-8. doi: 10.4238/vol9-1gmr721.

PubMed [citation]

PMID:: 20309827

See all PubMed Citations (6)

Details of each submission

From Natera, Inc., SCV001461038.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005204955.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: HBA2 c.142G>C (p.Asp48His), also reported as "hemoglobin Hasharon", "a2 47 his" and "Hasharon [47(CE5)Asp>His]", results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 126964 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HBA2 causing Alpha Thalassemia (9.5e-05 vs 0.0056). c.142G>C has been reported in the literature in multiple bi-allelic or heterozygous individuals affected with Alpha Thalassemia, microcytosis and hypochromia (examples: Gilad_ 2017, Kimura_ 2015, Silva_ 2013). The following publications have been ascertained in the context of this evaluation (PMID: 5780195, 28160324, 25818820, 7803274, 23741188, 20309827). ClinVar contains an entry for this variant (Variation ID: 15636). Based on the evidence outlined above, the variant was classified as 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

Last Updated: Oct 13, 2024

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