NM_000517.4(HBA2):c.142G>C (p.Asp48His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 15, 2022
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:: RCV001544589.23

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Homo sapiens MDS1 and EVI1 complex locus (MECOM), transcript variant 4, mRNA
Homo sapiens MDS1 and EVI1 complex locus (MECOM), transcript variant 4, mRNA
gi|1653962582|ref|NM_004991.4|

Nucleotide
2B [Enterovirus A]
2B [Enterovirus A]
gi|25121812|ref|NP_740531.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000885546	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Likely pathogenic (Oct 24, 2022)	germline	clinical testing	Citation Link,
SCV001763748	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 28, 2021)	germline	clinical testing	Citation Link,
SCV002047307	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Dec 15, 2022)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 7803274, 5713624, 25818820, 24200101, 27207683, 23741188, 18923834, 25130136, 28160324, 29403210, 5780195, 31553106, 31025160, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000885546

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Likely pathogenic
(Oct 24, 2022)

germline

clinical testing

Citation Link,

SCV001763748

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 28, 2021)

germline

clinical testing

Citation Link,

SCV002047307

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Dec 15, 2022)

unknown

clinical testing

PubMed (14)
[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
not provided	germline	yes	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

Hb Sinai, a new alpha chain mutant alpha his 47.

Ostertag W, Smith EW.

Humangenetik. 1968;6(4):377-9. No abstract available.

PubMed [citation]

PMID:: 5713624

See all PubMed Citations (14)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885546.7

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

Description

The Hb Hasharon variant (HBA2 c.142G>C; p.Asp48His variant, also known as Asp47His when numbered from the mature protein, HbVarID: 65, rs281864834), also known as Hb Sealy and Hb L-Ferrara, is reported in the literature in multiple families of Jewish, Italian and Middle Eastern descent (Charache 1969, Gilad 2017, Kimura 2015, Nagel 1969, Pich 1978, Schneider 1968). Individuals heterozygous for this variant have lower levels of the Hb Hasharon alpha chain than expected (Schneider 1968, Charache 1969), and some have been reported to have microcytosis and hypochromia (Kimura 2015). Functional characterization of Hb Hasharon indicates that the variant alpha chain has reduced stability in vitro (Charache 1969) and in vivo (Molchanova 1994). This variant is found in the general population with an overall allele frequency of 0.009% (12/126964 alleles) in the Genome Aggregation Database. The aspartate at codon 48 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL:0.789). Based on available information, the variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Charache S et al. Hemoglobin Hasharon (alpha-2-47 his(CD5)beta-2): a hemoglobin found in low concentration. J Clin Invest. 1969; 48(5):834-47. PMID: 5780195. Gilad O et al. Molecular diagnosis of alpha-thalassemia in a multiethnic population. Eur J Haematol. 2017 Jun;98(6):553-562. PMID: 28160324. Kimura E et al. Investigating alpha-globin structural variants: a retrospective review of 135,000 Brazilian individuals. Rev Bras Hematol Hemoter. 2015; 37(2):103-8. PMID: 25818820. Molchanova T et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994; 88(2):300-6. PMID: 7803274. Nagel R et al. Hemoglobin L Ferrara in a Jewish family associated with a hemolytic state in the propositus. Blood. 1969; 34(2):157-65. PMID: 5794113. Pich P et al. Interaction between Hb Hasharon and alpha-thalassemia: an approach to the problem of the number of human alpha loci. Blood. 1978; 51(2):339-46. PMID: 620088. Schneider R et al. Hemoglobin sealy (alpha 2-47His-beta 2): a new variant in a Jewish family. Am J Hum Genet. 1968; 20(2):151-6. PMID: 5643179.

#	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, SCV001763748.1

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

Description

Published functional studies demonstrate a damaging effect; in-vivo studies show percentage of the mutant Hb decreased with time, supporting instability of the mutant Hb in vivo (Charache et al., 1969); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25818820, 620088, 5643179, 5794113, 5780195, 2752146, 5587575, 28160324, 7803274, 31553106)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002047307.2

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

Description

The c.142G>C (p.Asp48His) variant has been reported to be mildly unstable (PMID: 5780195 (1969), 7803274 (1994)). Individuals who are heterozygous for this variant have normal clinical presentations. 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 13, 2024

ClinVar

Relating variation to medicine