ClinVar Genomic variation as it relates to human health
NM_000517.4(HBA2):c.142G>C (p.Asp48His)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)
9
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000517.4(HBA2):c.142G>C (p.Asp48His)
Variation ID: 15636 Accession: VCV000015636.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.3 16: 173171 (GRCh38) [ NCBI UCSC ] 16: 223170 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 26, 2018 Sep 16, 2024 Jun 10, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000517.6:c.142G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000508.1:p.Asp48His missense NC_000016.10:g.173171G>C NC_000016.9:g.223170G>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 LRG_1225:g.1521G>C LRG_1240:g.5325G>C LRG_1240t1:c.142G>C LRG_1240p1:p.Asp48His P69905:p.Asp48His - Protein change
- D48H
- Other names
-
D47H
Hb L-Ferrara
Hb Michigan-I
Hb Michigan-II
Hb Sealy
Hb Sinai
- Canonical SPDI
- NC_000016.10:173170:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00009
Exome Aggregation Consortium (ExAC) 0.00023
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| HBA2 | - | - |
GRCh38 GRCh37 |
4 | 346 | |
| LOC106804612 | - | - | - | GRCh38 | - | 283 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
|
HEMOGLOBIN HASHARON
|
other (1) |
no assertion criteria provided
|
May 21, 2018 | RCV000016911.11 |
|
HEMOGLOBIN SEALY
|
other (1) |
no assertion criteria provided
|
May 21, 2018 | RCV000016913.11 |
|
HEMOGLOBIN L (FERRARA)
|
other (1) |
no assertion criteria provided
|
May 21, 2018 | RCV000016910.11 |
|
HEMOGLOBIN SINAI
|
other (1) |
no assertion criteria provided
|
May 21, 2018 | RCV000016912.11 |
| Pathogenic (2) |
criteria provided, single submitter
|
Jun 10, 2024 | RCV001275680.10 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Dec 15, 2022 | RCV001544589.23 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001763748.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
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 … (more)
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) (less)
|
|
|
Likely pathogenic
(Oct 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885546.7
First in ClinVar: Feb 18, 2019 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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. (less)
|
|
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Uncertain significance
(Dec 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047307.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jun 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
alpha Thalassemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005204955.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
other
(May 21, 2018)
|
no assertion criteria provided
Method: literature only
|
HEMOGLOBIN L (FERRARA)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000037181.2
First in ClinVar: Apr 04, 2013 Last updated: May 26, 2018 |
Comment on evidence:
See Silvestroni et al. (1960, 1960), Bianco et al. (1963), Halbrecht et al. (1967), Ostertag and Smith (1968), Charache et al. (1969), Nagel et al. … (more)
See Silvestroni et al. (1960, 1960), Bianco et al. (1963), Halbrecht et al. (1967), Ostertag and Smith (1968), Charache et al. (1969), Nagel et al. (1969), Lehmann and Vella (1974), Tentori (1977), and Pich et al. (1978). The family in which hemoglobin Sealy was found was Ashkenazi (Schneider et al., 1968). (Hemoglobin Beilinson was also found in an Ashkenazi Jewish family and has a substitution of glycine for aspartic acid at alpha 47.) See Benesch et al. (1982). This is a mutation of the HBA2 gene (Cash et al., 1989). (less)
|
|
|
other
(May 21, 2018)
|
no assertion criteria provided
Method: literature only
|
HEMOGLOBIN HASHARON
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000037182.2
First in ClinVar: Apr 04, 2013 Last updated: May 26, 2018 |
Comment on evidence:
See Silvestroni et al. (1960, 1960), Bianco et al. (1963), Halbrecht et al. (1967), Ostertag and Smith (1968), Charache et al. (1969), Nagel et al. … (more)
See Silvestroni et al. (1960, 1960), Bianco et al. (1963), Halbrecht et al. (1967), Ostertag and Smith (1968), Charache et al. (1969), Nagel et al. (1969), Lehmann and Vella (1974), Tentori (1977), and Pich et al. (1978). The family in which hemoglobin Sealy was found was Ashkenazi (Schneider et al., 1968). (Hemoglobin Beilinson was also found in an Ashkenazi Jewish family and has a substitution of glycine for aspartic acid at alpha 47.) See Benesch et al. (1982). This is a mutation of the HBA2 gene (Cash et al., 1989). (less)
|
|
|
other
(May 21, 2018)
|
no assertion criteria provided
Method: literature only
|
HEMOGLOBIN SEALY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000037184.2
First in ClinVar: Apr 04, 2013 Last updated: May 26, 2018 |
Comment on evidence:
See Silvestroni et al. (1960, 1960), Bianco et al. (1963), Halbrecht et al. (1967), Ostertag and Smith (1968), Charache et al. (1969), Nagel et al. … (more)
See Silvestroni et al. (1960, 1960), Bianco et al. (1963), Halbrecht et al. (1967), Ostertag and Smith (1968), Charache et al. (1969), Nagel et al. (1969), Lehmann and Vella (1974), Tentori (1977), and Pich et al. (1978). The family in which hemoglobin Sealy was found was Ashkenazi (Schneider et al., 1968). (Hemoglobin Beilinson was also found in an Ashkenazi Jewish family and has a substitution of glycine for aspartic acid at alpha 47.) See Benesch et al. (1982). This is a mutation of the HBA2 gene (Cash et al., 1989). (less)
|
|
|
other
(May 21, 2018)
|
no assertion criteria provided
Method: literature only
|
HEMOGLOBIN SINAI
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000037183.2
First in ClinVar: Apr 04, 2013 Last updated: May 26, 2018 |
Comment on evidence:
See Silvestroni et al. (1960, 1960), Bianco et al. (1963), Halbrecht et al. (1967), Ostertag and Smith (1968), Charache et al. (1969), Nagel et al. … (more)
See Silvestroni et al. (1960, 1960), Bianco et al. (1963), Halbrecht et al. (1967), Ostertag and Smith (1968), Charache et al. (1969), Nagel et al. (1969), Lehmann and Vella (1974), Tentori (1977), and Pich et al. (1978). The family in which hemoglobin Sealy was found was Ashkenazi (Schneider et al., 1968). (Hemoglobin Beilinson was also found in an Ashkenazi Jewish family and has a substitution of glycine for aspartic acid at alpha 47.) See Benesch et al. (1982). This is a mutation of the HBA2 gene (Cash et al., 1989). (less)
|
|
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Likely pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Alpha thalassemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001461038.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Citation text
Silvestroni, E., Bianco, I., Lucci, R., Soffritti, E. Presence of hemoglobin 'L' in natives of Ferrara and of hemoglobin 'D' in natives of Bologna. Acta Genet. Med. Gemellol. 9: 472-496, 1960.
Citation text
Silvestroni, E., Bianco, I., Lucci, R., Soffritti, E. The hematological picture in carriers of Hb L, living in Ferrara: associations and relations to microcythemia. Prog. Med. 16: 553-561, 1960.
Citation text
Lehmann, H. Haemoglobins and haemoglobinopathies. In: Lehmann, H., Betke, K. Haemoglobin-Colloquium. Stuttgart: Georg Thieme Verlag (pub.) 1-14, 1962.
Citation text
Tentori, L. Hemoglobin L Ferrara = hemoglobin Hasharon. Hemoglobin 1: 602, 1977.
Citation text
Schneider, R. G. Personal Communication. 1974. Galveston, Tex.
Citation text
Silvestroni, E., Bianco, I., Lucci, R., Soffritti, E. Presence of hemoglobin 'L' in natives of Ferrara and of hemoglobin 'D' in natives of Bologna. Acta Genet. Med. Gemellol. 9: 472-496, 1960.
Citation text
Silvestroni, E., Bianco, I., Lucci, R., Soffritti, E. The hematological picture in carriers of Hb L, living in Ferrara: associations and relations to microcythemia. Prog. Med. 16: 553-561, 1960.
Citation text
Lehmann, H. Haemoglobins and haemoglobinopathies. In: Lehmann, H., Betke, K. Haemoglobin-Colloquium. Stuttgart: Georg Thieme Verlag (pub.) 1-14, 1962.
Citation text
Tentori, L. Hemoglobin L Ferrara = hemoglobin Hasharon. Hemoglobin 1: 602, 1977.
Citation text
Schneider, R. G. Personal Communication. 1974. Galveston, Tex.
Citation text
Silvestroni, E., Bianco, I., Lucci, R., Soffritti, E. Presence of hemoglobin 'L' in natives of Ferrara and of hemoglobin 'D' in natives of Bologna. Acta Genet. Med. Gemellol. 9: 472-496, 1960.
Citation text
Silvestroni, E., Bianco, I., Lucci, R., Soffritti, E. The hematological picture in carriers of Hb L, living in Ferrara: associations and relations to microcythemia. Prog. Med. 16: 553-561, 1960.
Citation text
Lehmann, H. Haemoglobins and haemoglobinopathies. In: Lehmann, H., Betke, K. Haemoglobin-Colloquium. Stuttgart: Georg Thieme Verlag (pub.) 1-14, 1962.
Citation text
Tentori, L. Hemoglobin L Ferrara = hemoglobin Hasharon. Hemoglobin 1: 602, 1977.
Citation text
Schneider, R. G. Personal Communication. 1974. Galveston, Tex.
Citation text
Silvestroni, E., Bianco, I., Lucci, R., Soffritti, E. Presence of hemoglobin 'L' in natives of Ferrara and of hemoglobin 'D' in natives of Bologna. Acta Genet. Med. Gemellol. 9: 472-496, 1960.
Citation text
Silvestroni, E., Bianco, I., Lucci, R., Soffritti, E. The hematological picture in carriers of Hb L, living in Ferrara: associations and relations to microcythemia. Prog. Med. 16: 553-561, 1960.
Citation text
Lehmann, H. Haemoglobins and haemoglobinopathies. In: Lehmann, H., Betke, K. Haemoglobin-Colloquium. Stuttgart: Georg Thieme Verlag (pub.) 1-14, 1962.
Citation text
Tentori, L. Hemoglobin L Ferrara = hemoglobin Hasharon. Hemoglobin 1: 602, 1977.
Citation text
Schneider, R. G. Personal Communication. 1974. Galveston, Tex.
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Curating the gnomAD database: Report of novel variants in the globin-coding genes and bioinformatics analysis. | Scheps KG | Human mutation | 2020 | PMID: 31553106 |
| Characterization of deletional and non-deletional alpha globin variants in a large cohort from Spain between 2009 and 2014. | de la Fuente-Gonzalo F | Annals of hematology | 2019 | PMID: 31025160 |
| Prevalence of hemoglobin variants and hemoglobinopathies using cation-exchange high-performance liquid chromatography in central reference laboratory of India: A report of 65779 cases. | Warghade S | Journal of laboratory physicians | 2018 | PMID: 29403210 |
| Molecular diagnosis of α-thalassemia in a multiethnic population. | Gilad O | European journal of haematology | 2017 | PMID: 28160324 |
| Report on Ten Years' Experience of Premarital Hemoglobinopathy Screening at a Center in Antalya, Southern Turkey. | Canatan D | Hemoglobin | 2016 | PMID: 27207683 |
| Investigating alpha-globin structural variants: a retrospective review of 135,000 Brazilian individuals. | Kimura EM | Revista brasileira de hematologia e hemoterapia | 2015 | PMID: 25818820 |
| Improvements in phenotype studies of hemoglobin disorders brought by advances in reversed-phase chromatography of globin chains. | Riou J | International journal of laboratory hematology | 2015 | PMID: 25130136 |
| Hemoglobin analyses in the Netherlands reveal more than 80 different variants including six novel ones. | van Zwieten R | Hemoglobin | 2014 | PMID: 24200101 |
| Alpha chain hemoglobins with electrophoretic mobility similar to that of hemoglobin S in a newborn screening program. | Silva MR | Revista brasileira de hematologia e hemoterapia | 2013 | PMID: 23741188 |
| Abnormal hemoglobin phenotypes in carriers of mild anemia in Latin America. | Zamaro PJ | Genetics and molecular research : GMR | 2010 | PMID: 20309827 |
| Mutations in the paralogous human alpha-globin genes yielding identical hemoglobin variants. | Moradkhani K | Annals of hematology | 2009 | PMID: 18923834 |
| The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. | Molchanova TP | British journal of haematology | 1994 | PMID: 7803274 |
| Locus assignment of two alpha-globin structural mutants from the Caribbean basin: alpha Fort de France (alpha 45 Arg) and alpha Spanish Town (alpha 27 Val). | Cash FE | Blood | 1989 | PMID: 2752146 |
| The effects of alpha chain mutations cis and trans to the beta6 mutation on the polymerization of sickle cell haemoglobin. | Benesch RE | Nature | 1982 | PMID: 7110343 |
| Interaction between Hb Hasharon and alpha-thalassemia: an approach to the problem of the number of human alpha loci. | Pich P | Blood | 1978 | PMID: 620088 |
| Hemoglobin L Ferrara in a Jewish family associated with a hemolytic state in the propositus. | Nagel RL | Blood | 1969 | PMID: 5794113 |
| Hemoglobin Hasharon (alpha-2-47 his(CD5)beta-2): a hemoglobin found in low concentration. | Charache S | The Journal of clinical investigation | 1969 | PMID: 5780195 |
| Hb Sinai, a new alpha chain mutant alpha his 47. | Ostertag W | Humangenetik | 1968 | PMID: 5713624 |
| Hemoglobin hasharon (alpha-47 aspartic acid--histidine). | Halbrecht I | Israel journal of medical sciences | 1967 | PMID: 5587575 |
| Alternation in the alpha-chain of haemoglobin L-Ferrara. | BIANCO I | Nature | 1963 | PMID: 13968068 |
| Lehmann, H. Haemoglobins and haemoglobinopathies. In: Lehmann, H., Betke, K. Haemoglobin-Colloquium. Stuttgart: Georg Thieme Verlag (pub.) 1-14, 1962. | - | - | - | - |
| Schneider, R. G. Personal Communication. 1974. Galveston, Tex. | - | - | - | - |
| Silvestroni, E., Bianco, I., Lucci, R., Soffritti, E. Presence of hemoglobin 'L' in natives of Ferrara and of hemoglobin 'D' in natives of Bologna. Acta Genet. Med. Gemellol. 9: 472-496, 1960. | - | - | - | - |
| Silvestroni, E., Bianco, I., Lucci, R., Soffritti, E. The hematological picture in carriers of Hb L, living in Ferrara: associations and relations to microcythemia. Prog. Med. 16: 553-561, 1960. | - | - | - | - |
| Tentori, L. Hemoglobin L Ferrara = hemoglobin Hasharon. Hemoglobin 1: 602, 1977. | - | - | - | - |
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Text-mined citations for rs281864834 ...
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Record last updated Nov 25, 2024
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