The HBA2 c.89T>C; p.Leu30Pro variant (also known as Hb Agrinio or Leu29Pro when numbered from the mature protein, rs41341344, HbVar ID:45) has been reported in multiple individuals with microcytosis and hypochromia when found in a heterozygous state (de la Fuente-Gonzalo 2012, Hall 1993). Individuals homozygous for this variant or compound heterozygous with another pathogenic variant exhibit marked hypochromic microcytic anemia, with an elevated reticulocyte count and occasionally elevated Hb Barts or Hb H (de la Fuente-Gonzalo 2012, Hall 1993). This variant is also reported in ClinVar (Variation ID: 15651), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 30 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.910). In vitro studies show the variant protein is undetectable by various analyses, suggestive of an unstable hemoglobin variant (Hall 1993). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html de la Fuente-Gonzalo F et al. Study of three families with Hb Agrinio (alpha29(B10)Leu?Pro, CTG>CCG (alpha2)) in the Spanish population: three homozygous cases. Hemoglobin. 2012; 36(6):526-32. Hall G et al. A base substitution (T-->C) in codon 29 of the alpha 2-globin gene causes alpha thalassaemia. Br J Haematol. 1993; 85(3):546-52.
ClinVar Genomic variation as it relates to human health
NM_000517.6(HBA2):c.89T>C (p.Leu30Pro)
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.
(5)
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.
Pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000517.6(HBA2):c.89T>C (p.Leu30Pro)
Variation ID: 15651 Accession: VCV000015651.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 173001 (GRCh38) [ NCBI UCSC ] 16: 223000 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Sep 16, 2024 Jul 8, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000517.6:c.89T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000508.1:p.Leu30Pro missense NC_000016.10:g.173001T>C NC_000016.9:g.223000T>C NG_000006.1:g.33864T>C NG_046165.1:g.2740T>C NG_059186.1:g.1351T>C NG_059271.1:g.5155T>C LRG_1225:g.1351T>C LRG_1240:g.5155T>C LRG_1240t1:c.89T>C LRG_1240p1:p.Leu30Pro - Protein change
- L30P
- Other names
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L29P
- Canonical SPDI
- NC_000016.10:173000:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
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| 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. |
|---|---|---|---|---|
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HEMOGLOBIN AGRINIO
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other (1) |
no assertion criteria provided
|
Sep 12, 2022 | RCV000016937.2 |
| Pathogenic (1) |
no assertion criteria provided
|
May 1, 1998 | RCV000022605.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 27, 2022 | RCV000759059.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 8, 2024 | RCV004700242.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jul 09, 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: SCV003800217.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The HBA2 c.89T>C; p.Leu30Pro variant (also known as Hb Agrinio or Leu29Pro when numbered from the mature protein, rs41341344, HbVar ID:45) has been reported in … (more)
The HBA2 c.89T>C; p.Leu30Pro variant (also known as Hb Agrinio or Leu29Pro when numbered from the mature protein, rs41341344, HbVar ID:45) has been reported in multiple individuals with microcytosis and hypochromia when found in a heterozygous state (de la Fuente-Gonzalo 2012, Hall 1993). Individuals homozygous for this variant or compound heterozygous with another pathogenic variant exhibit marked hypochromic microcytic anemia, with an elevated reticulocyte count and occasionally elevated Hb Barts or Hb H (de la Fuente-Gonzalo 2012, Hall 1993). This variant is also reported in ClinVar (Variation ID: 15651), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 30 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.910). In vitro studies show the variant protein is undetectable by various analyses, suggestive of an unstable hemoglobin variant (Hall 1993). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html de la Fuente-Gonzalo F et al. Study of three families with Hb Agrinio (alpha29(B10)Leu?Pro, CTG>CCG (alpha2)) in the Spanish population: three homozygous cases. Hemoglobin. 2012; 36(6):526-32. Hall G et al. A base substitution (T-->C) in codon 29 of the alpha 2-globin gene causes alpha thalassaemia. Br J Haematol. 1993; 85(3):546-52. (less)
|
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Pathogenic
(Jul 08, 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: SCV005203220.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: HBA2 c.89T>C (p.Leu30Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: HBA2 c.89T>C (p.Leu30Pro) results in a non-conservative amino acid change in 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 2.2e-06 in 446884 control chromosomes (gnomAD v4.1). c.89T>C has been reported in the literature in the simple heterozygous state in individuals with alpha thalassemia and in compound heterozygotes with an atypical form of HbH disease characterized by a severe hypochromic microcytic anaemia (Hall_1993). It was also found in the homozygous state in multuple cases of severe antenatal anemia (Szepetowski_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36052950, 8136277). ClinVar contains an entry for this variant (Variation ID: 15651). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Oct 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888140.3
First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024 |
Comment:
The c.89T>C (p.Leu30Pro) mutation in the alpha2-globin gene is known as Hb Agrinio. Hb Agrinio is reported as being hyperunstable. Individuals who are heterozygous for … (more)
The c.89T>C (p.Leu30Pro) mutation in the alpha2-globin gene is known as Hb Agrinio. Hb Agrinio is reported as being hyperunstable. Individuals who are heterozygous for this variant are reported as having a normal clinical presentation (PMID: 8537235 (1995)). However, individuals who are homozygous for this variant, or compound heterozygous for this variant and a mutation associated with alpha-thalassemia, often present with atypical Hb H disease (PMIDs: 36052950 (2022), 29219637 (2017), 23094635 (2012), 22452522 (2012), 20854116 (2010), 9629496 (1998), 8537235 (1995), and 8136277 (1993)). (less)
|
|
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other
(Sep 12, 2022)
|
no assertion criteria provided
Method: literature only
|
HEMOGLOBIN AGRINIO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000037208.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 17, 2022 |
Comment on evidence:
Hb Agrinio was discovered by Hall et al. (1993) in 3 individuals of Greek origin with an atypical form of Hb H disease (613978) characterized … (more)
Hb Agrinio was discovered by Hall et al. (1993) in 3 individuals of Greek origin with an atypical form of Hb H disease (613978) characterized by a severe hypochromic, microcytic anemia. Hall et al. (1993) indicated that the mutation consisted of a T-to-C transition in codon 29 of the HBA2 gene causing a leucine-to-proline transition. Although each affected individual was a compound heterozygote for Hb Agrinio and a previously described mutation affecting the poly(A) addition signal of the HBB gene (141900.0383), simple heterozygotes for the leu29-to-pro mutation have the phenotype of the alpha-thalassemia trait. Traeger-Synodinos et al. (1998) reported the first case of homozygosity for Hb Agrinio. The leu29-to-pro amino acid substitution in alpha-2-globin was caused by a CTG-to-CCG transition. The 12-month-old Greek proband presented with marked hypochromic microcytic anemia, a very low level of Hb H, rare Hb H inclusions, and a balanced alpha/non-alpha biosynthesis ratio. At the age of 13 years, the proband had a clinical phenotype compatible with mild thalassemia intermedia with moderate anemia (Hb = 7-8 g/dL), normal growth and development, slight splenomegaly, and minimal bone changes, while Hb H and inclusion bodies were not detected. (less)
|
|
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Pathogenic
(May 01, 1998)
|
no assertion criteria provided
Method: literature only
|
HEMOGLOBIN H DISEASE, NONDELETIONAL
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000043894.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 17, 2022 |
Comment on evidence:
Hb Agrinio was discovered by Hall et al. (1993) in 3 individuals of Greek origin with an atypical form of Hb H disease (613978) characterized … (more)
Hb Agrinio was discovered by Hall et al. (1993) in 3 individuals of Greek origin with an atypical form of Hb H disease (613978) characterized by a severe hypochromic, microcytic anemia. Hall et al. (1993) indicated that the mutation consisted of a T-to-C transition in codon 29 of the HBA2 gene causing a leucine-to-proline transition. Although each affected individual was a compound heterozygote for Hb Agrinio and a previously described mutation affecting the poly(A) addition signal of the HBB gene (141900.0383), simple heterozygotes for the leu29-to-pro mutation have the phenotype of the alpha-thalassemia trait. Traeger-Synodinos et al. (1998) reported the first case of homozygosity for Hb Agrinio. The leu29-to-pro amino acid substitution in alpha-2-globin was caused by a CTG-to-CCG transition. The 12-month-old Greek proband presented with marked hypochromic microcytic anemia, a very low level of Hb H, rare Hb H inclusions, and a balanced alpha/non-alpha biosynthesis ratio. At the age of 13 years, the proband had a clinical phenotype compatible with mild thalassemia intermedia with moderate anemia (Hb = 7-8 g/dL), normal growth and development, slight splenomegaly, and minimal bone changes, while Hb H and inclusion bodies were not detected. (less)
|
Comment:
Comment:
Variant summary: HBA2 c.89T>C (p.Leu30Pro) results in a non-conservative amino acid change in 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 2.2e-06 in 446884 control chromosomes (gnomAD v4.1). c.89T>C has been reported in the literature in the simple heterozygous state in individuals with alpha thalassemia and in compound heterozygotes with an atypical form of HbH disease characterized by a severe hypochromic microcytic anaemia (Hall_1993). It was also found in the homozygous state in multuple cases of severe antenatal anemia (Szepetowski_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36052950, 8136277). ClinVar contains an entry for this variant (Variation ID: 15651). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The c.89T>C (p.Leu30Pro) mutation in the alpha2-globin gene is known as Hb Agrinio. Hb Agrinio is reported as being hyperunstable. Individuals who are heterozygous for this variant are reported as having a normal clinical presentation (PMID: 8537235 (1995)). However, individuals who are homozygous for this variant, or compound heterozygous for this variant and a mutation associated with alpha-thalassemia, often present with atypical Hb H disease (PMIDs: 36052950 (2022), 29219637 (2017), 23094635 (2012), 22452522 (2012), 20854116 (2010), 9629496 (1998), 8537235 (1995), and 8136277 (1993)).
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:
The HBA2 c.89T>C; p.Leu30Pro variant (also known as Hb Agrinio or Leu29Pro when numbered from the mature protein, rs41341344, HbVar ID:45) has been reported in multiple individuals with microcytosis and hypochromia when found in a heterozygous state (de la Fuente-Gonzalo 2012, Hall 1993). Individuals homozygous for this variant or compound heterozygous with another pathogenic variant exhibit marked hypochromic microcytic anemia, with an elevated reticulocyte count and occasionally elevated Hb Barts or Hb H (de la Fuente-Gonzalo 2012, Hall 1993). This variant is also reported in ClinVar (Variation ID: 15651), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 30 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.910). In vitro studies show the variant protein is undetectable by various analyses, suggestive of an unstable hemoglobin variant (Hall 1993). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html de la Fuente-Gonzalo F et al. Study of three families with Hb Agrinio (alpha29(B10)Leu?Pro, CTG>CCG (alpha2)) in the Spanish population: three homozygous cases. Hemoglobin. 2012; 36(6):526-32. Hall G et al. A base substitution (T-->C) in codon 29 of the alpha 2-globin gene causes alpha thalassaemia. Br J Haematol. 1993; 85(3):546-52.
Comment:
Variant summary: HBA2 c.89T>C (p.Leu30Pro) results in a non-conservative amino acid change in 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 2.2e-06 in 446884 control chromosomes (gnomAD v4.1). c.89T>C has been reported in the literature in the simple heterozygous state in individuals with alpha thalassemia and in compound heterozygotes with an atypical form of HbH disease characterized by a severe hypochromic microcytic anaemia (Hall_1993). It was also found in the homozygous state in multuple cases of severe antenatal anemia (Szepetowski_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36052950, 8136277). ClinVar contains an entry for this variant (Variation ID: 15651). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The c.89T>C (p.Leu30Pro) mutation in the alpha2-globin gene is known as Hb Agrinio. Hb Agrinio is reported as being hyperunstable. Individuals who are heterozygous for this variant are reported as having a normal clinical presentation (PMID: 8537235 (1995)). However, individuals who are homozygous for this variant, or compound heterozygous for this variant and a mutation associated with alpha-thalassemia, often present with atypical Hb H disease (PMIDs: 36052950 (2022), 29219637 (2017), 23094635 (2012), 22452522 (2012), 20854116 (2010), 9629496 (1998), 8537235 (1995), and 8136277 (1993)).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Homozygosity for the hyperunstable hemoglobin variant Hb Agrinio (HBA2:c.89T>C) leads to severe antenatal anemia: Eight new cases in three families. | Szepetowski S | American journal of hematology | 2022 | PMID: 36052950 |
| α-Globin Genotypes Associated with Hb H Disease: A Report from Oman and a Review of the Literature from the Eastern Mediterranean Region. | Al-Riyami AZ | Hemoglobin | 2020 | PMID: 32019385 |
| First Cases of Hb Agrinio Described in Patients from the Republic of Macedonia. | Dimishkovska M | Hemoglobin | 2017 | PMID: 29219637 |
| Screening non-deletion α-thalassaemia mutations in the HBA1 and HBA2 genes by high-resolution melting analysis. | Petropoulou M | Clinical chemistry and laboratory medicine | 2015 | PMID: 26035111 |
| Hb Dartmouth (HBA2: c.200T>C): An α2-Globin Gene Associated with Hb H Disease in One Homozygous Patient. | Farashi S | Hemoglobin | 2015 | PMID: 25976777 |
| Multi-allele DNA biosensor for the rapid genotyping of 'nondeletion' alpha thalassaemia mutations in HBA1 and HBA2 genes by means of multiplex primer extension reaction. | Petropoulou M | Clinica chimica acta; international journal of clinical chemistry | 2015 | PMID: 25892676 |
| Study of three families with Hb Agrinio [α29(B10)Leu→Pro, CTG>CCG (α2)] in the Spanish population: three homozygous cases. | de la Fuente-Gonzalo F | Hemoglobin | 2012 | PMID: 23094635 |
| Microsatellite markers within the α-globin gene cluster for robust preimplantation genetic diagnosis of severe α-thalassemia syndromes in Mediterranean populations. | Destouni A | Hemoglobin | 2012 | PMID: 22452522 |
| A dyserythropoietic anemia associated with homozygous Hb Plasencia [α125(H8)Leu→Arg (α2)] (HBA2:c.377T>G), a variant with an unstable α chain. | Garçon L | Hemoglobin | 2010 | PMID: 21077766 |
| Variable and often severe phenotypic expression in patients with the α-thalassemic variant Hb Agrinio [α29(B10)Leu→Pro (α2)]. | Traeger-Synodinos J | Hemoglobin | 2010 | PMID: 20854116 |
| An alpha-thalassemic hemoglobinopathy: homozygosity for the HB Agrinio alpha 2-globin chain variant. | Traeger-Synodinos J | Hemoglobin | 1998 | PMID: 9629496 |
| Hb A2-Agrinio [delta 43(CD2)Glu-->Gly(GAG-->GGG)]: a new delta chain variant detected in a Greek family. | Papadakis M | Hemoglobin | 1995 | PMID: 8537235 |
| A base substitution (T-->C) in codon 29 of the alpha 2-globin gene causes alpha thalassaemia. | Hall GW | British journal of haematology | 1993 | PMID: 8136277 |
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Text-mined citations for rs41341344 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.