VCV000015630.19 - ClinVar

NM_000517.6(HBA2):c.377T>C (p.Leu126Pro)

Germline

Classification

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.

(7)

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

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.377T>C (p.Leu126Pro)

Variation ID: 15630 Accession: VCV000015630.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 173548 (GRCh38) [ NCBI UCSC ] 16: 223547 (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	Apr 4, 2013	Sep 29, 2024	Feb 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000517.6:c.377T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000508.1:p.Leu126Pro	missense
NC_000016.10:g.173548T>C
NC_000016.9:g.223547T>C
NG_000006.1:g.34411T>C
NG_046165.1:g.3287T>C
NG_059186.1:g.1898T>C
NG_059271.1:g.5702T>C
LRG_1225:g.1898T>C
LRG_1240:g.5702T>C
LRG_1240t1:c.377T>C	LRG_1240p1:p.Leu126Pro
	P69905:p.Leu126Pro

... more HGVS ... less HGVS

Protein change

L126P

Other names

L125P
Alpha2 Leu125Pro

Canonical SPDI

NC_000016.10:173547:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

1000 Genomes Project 30x 0.00016

Links

ClinGen: CA125557 UniProtKB: P69905#VAR_002836 OMIM: 141850.0005 dbSNP: rs41397847 VarSome

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
Gene	OMIM	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 Quong Sze	other (1)	no assertion criteria provided	Mar 28, 2013	RCV000016897.9
alpha Thalassemia	Pathogenic (2)	no assertion criteria provided	Jan 8, 2021	RCV000417220.11
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 16, 2024	RCV001811168.18
Erythrocytosis, familial, 7 Heinz body anemia Hemoglobin H disease alpha Thalassemia	Pathogenic (1)	criteria provided, single submitter	May 9, 2022	RCV002476982.8

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 (May 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Heinz body anemia alpha Thalassemia Hemoglobin H disease Erythrocytosis, familial, 7 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002780035.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 14, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004219830.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (12) PubMed: 7070526‚ 21797711‚ 25523870‚ 19259674‚ 26956449‚ 28125089‚ 6826718‚ 1726096‚ 7515267‚ 31553106‚ 31286593‚ 30275481 Comment: The c.377T>C (p.Leu126Pro) pathogenic variant (also known as Hb Quong Sze) is reported as being highly unstable (PMID: 6826718 (1983), 1726096 (1991)). The frequency of … (more) The c.377T>C (p.Leu126Pro) pathogenic variant (also known as Hb Quong Sze) is reported as being highly unstable (PMID: 6826718 (1983), 1726096 (1991)). The frequency of this variant in the general population, 0.00071 (13/18322 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals who are compound heterozygous for this pathogenic variant and a large deletion that removes both of the alpha-globin genes from the alpha-globin gene cluster (e.g., the --SEA alpha-globin deletion) are reported as being affected by Hb H disease (PMID: 7070526 (1982), 7515267 (1994), 19259674 (2009)). (less)
Pathogenic (Oct 27, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159864.6 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024	Comment: The Hb Quong Sze variant (HBA2: c.377T>C; p.Leu126Pro, also known as Leu125Pro when numbered from the mature protein, rs41397847, HbVar ID: 187) is reported in … (more) The Hb Quong Sze variant (HBA2: c.377T>C; p.Leu126Pro, also known as Leu125Pro when numbered from the mature protein, rs41397847, HbVar ID: 187) is reported in the literature in multiple Chinese individuals and families affected with alpha thalassemia (see link to HbVar and references therein). This variant has been observed in the heterozygous state in individuals with a clinical presentation resembling alpha-thalassemia trait, and in the compound heterozygous state with other pathogenic hemoglobin variants in individuals affected with hemoglobin H disease (Ahmad 2013, Goossens 1982, He 2017, Li 2011, Li 2015, Liang 1994, Liao 2009, Shang 2017, Zhou 2016). In vitro/in vivo functional analyses demonstrate that the variant protein is turned over rapidly and interferes with the formation of hemoglobin tetramers (Liebhaber 1983). This variant is reported in ClinVar (Variation ID: 15630). This variant is found in the East Asian population with an overall allele frequency of 0.08% (13/18322 alleles, including a single homozygote) in the Genome Aggregation Database. Additionally, other variants at this codon Hb West-Einde (HbVar ID: 2592), and Hb Plasencia (HbVar ID: 1226) have been reported in individuals with mild to moderate anemia, microcytosis, and hypochromia (see links to HbVar and references therein). The leucine at codon 126 is weakly conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.854). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Ahmad R et al. Distribution of alpha thalassaemia gene variants in diverse ethnic populations in malaysia: data from the institute for medical research. Int J Mol Sci. 2013 Sep 10;14(9):18599-614. PMID: 24025420 Goossens M et al. Globin structural mutant alpha 125Leu leads to Pro is a novel cause of alpha-thalassaemia. Nature. 1982 Apr 29;296(5860):864-5. PMID: 7070526 He J et al. Next-generation sequencing improves thalassemia carrier screening among premarital adults in a high prevalence population: the Dai nationality, China. Genet Med. 2017 Sep;19(9):1022-1031. PMID: 28125089 Li J et al. Phenotypic variability in a chinese family with nondeletional Hb H-Hb Quong Sze disease. Hemoglobin. 2011;35(4):430-3. PMID: 21797711 Li J et al. Identification of nondeletional a-thalassemia in a prenatal screening program by reverse dot-blot in southern China. Hemoglobin. 2015;39(1):42-5. PMID: 25523870 Liang R et al. Alpha and beta thalassaemia among Chinese children in Guangxi Province, P.R. China: molecular and haematological characterization. Br J Haematol. 1994 Feb;86(2):351-4. PMID: 7515267 Liao C et al. Diversity in clinical presentation of hemoglobin H disease induced by the SEA deletion and the hemoglobin Quong Sze. Ann Hematol. 2009 Nov;88(11):1145-7. PMID: 19259674 Liebhaber SA et al. alpha-Thalassemia caused by an unstable alpha-globin mutant. J Clin Invest. 1983 Mar;71(3):461-6. PMID: 6826718 Shang X et al. Rapid Targeted Next-Generation Sequencing Platform for Molecular Screening and Clinical Genotyping in Subjects with Hemoglobinopathies. EBioMedicine. 2017 Sep;23:150-159. PMID: 28865746 Zhou JY et al. First Case of a Compound Heterozygosity for Two Nondeletional a-Thalassemia mutations, Hb Constant Spring and Hb Quong Sze. Hemoglobin. 2016 Jun;40(3):210-2. PMID: 26956449 (less)
Pathogenic (Feb 16, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325101.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Also known as Hb Quong Sze, Hb QS, p.L125P; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published … (more) Also known as Hb Quong Sze, Hb QS, p.L125P; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect and results in an unstable hemoglobin alpha molecule (PMID: 6826718); This variant is associated with the following publications: (PMID: 7070526, 34334003, 36059093, 32830468, 36900038, 26956449, 22589661, 28674233, 21797711, 1726096, 909565, 30275481, 19259674, 31553106, 25523870, 38123349, 24081251, 32811243, 28865746, 7515267, 23383304, SuwannasingS2016[Article], 32436451, 38112059, 32473995, 36685902, 24985555, 20144601, 32338097, 28125089, 11325652, Vijian2022[Review], 31111755, 24826791, WidyastitiNS2019[Article], 25352644, 6826718) (less)
other (Mar 28, 2013)	no assertion criteria provided Method: literature only	HEMOGLOBIN QUONG SZE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037168.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 7070526‚ 1726096 Comment on evidence: Goossens et al. (1982) described another nondeletion mechanism: mutation in the 125th codon of the alpha-2 gene resulted in substitution of proline for leucine in … (more) Goossens et al. (1982) described another nondeletion mechanism: mutation in the 125th codon of the alpha-2 gene resulted in substitution of proline for leucine in a region of the H helix of the alpha-globin chain, which is critical for alpha-beta contact, resulting in impediment to alpha-beta dimer formation, the initial step in hemoglobin tetramer assembly. Thus, the alpha-thalassemia phenotype results from a novel posttranslational mechanism. Goossens et al. (1982) named the mutant Quong Sze, after the province in China where the mother of their proband was born. Liang et al. (1991) reported a second example of this mutation in a Chinese family in Guangxi (Quong Sze). Hb Quong Sze is a highly unstable alpha-chain variant; because the abnormal alpha chains are rapidly catabolized, the abnormal hemoglobin is difficult to detect in reticulocytes. Identification was made through gene analysis. (less)
Pathogenic (Jan 08, 2021)	no assertion criteria provided Method: clinical testing	Alpha thalassemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002093848.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
not provided (-)	no classification provided Method: literature only	alpha Thalassemia Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000503051.2 First in ClinVar: Mar 02, 2017 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1435 BookShelf: NBK1435

Comment:

The c.377T>C (p.Leu126Pro) pathogenic variant (also known as Hb Quong Sze) is reported as being highly unstable (PMID: 6826718 (1983), 1726096 (1991)). The frequency of this variant in the general population, 0.00071 (13/18322 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals who are compound heterozygous for this pathogenic variant and a large deletion that removes both of the alpha-globin genes from the alpha-globin gene cluster (e.g., the --SEA alpha-globin deletion) are reported as being affected by Hb H disease (PMID: 7070526 (1982), 7515267 (1994), 19259674 (2009)).

Comment:

The Hb Quong Sze variant (HBA2: c.377T>C; p.Leu126Pro, also known as Leu125Pro when numbered from the mature protein, rs41397847, HbVar ID: 187) is reported in the literature in multiple Chinese individuals and families affected with alpha thalassemia (see link to HbVar and references therein). This variant has been observed in the heterozygous state in individuals with a clinical presentation resembling alpha-thalassemia trait, and in the compound heterozygous state with other pathogenic hemoglobin variants in individuals affected with hemoglobin H disease (Ahmad 2013, Goossens 1982, He 2017, Li 2011, Li 2015, Liang 1994, Liao 2009, Shang 2017, Zhou 2016). In vitro/in vivo functional analyses demonstrate that the variant protein is turned over rapidly and interferes with the formation of hemoglobin tetramers (Liebhaber 1983). This variant is reported in ClinVar (Variation ID: 15630). This variant is found in the East Asian population with an overall allele frequency of 0.08% (13/18322 alleles, including a single homozygote) in the Genome Aggregation Database. Additionally, other variants at this codon Hb West-Einde (HbVar ID: 2592), and Hb Plasencia (HbVar ID: 1226) have been reported in individuals with mild to moderate anemia, microcytosis, and hypochromia (see links to HbVar and references therein). The leucine at codon 126 is weakly conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.854). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Ahmad R et al. Distribution of alpha thalassaemia gene variants in diverse ethnic populations in malaysia: data from the institute for medical research. Int J Mol Sci. 2013 Sep 10;14(9):18599-614. PMID: 24025420 Goossens M et al. Globin structural mutant alpha 125Leu leads to Pro is a novel cause of alpha-thalassaemia. Nature. 1982 Apr 29;296(5860):864-5. PMID: 7070526 He J et al. Next-generation sequencing improves thalassemia carrier screening among premarital adults in a high prevalence population: the Dai nationality, China. Genet Med. 2017 Sep;19(9):1022-1031. PMID: 28125089 Li J et al. Phenotypic variability in a chinese family with nondeletional Hb H-Hb Quong Sze disease. Hemoglobin. 2011;35(4):430-3. PMID: 21797711 Li J et al. Identification of nondeletional a-thalassemia in a prenatal screening program by reverse dot-blot in southern China. Hemoglobin. 2015;39(1):42-5. PMID: 25523870 Liang R et al. Alpha and beta thalassaemia among Chinese children in Guangxi Province, P.R. China: molecular and haematological characterization. Br J Haematol. 1994 Feb;86(2):351-4. PMID: 7515267 Liao C et al. Diversity in clinical presentation of hemoglobin H disease induced by the SEA deletion and the hemoglobin Quong Sze. Ann Hematol. 2009 Nov;88(11):1145-7. PMID: 19259674 Liebhaber SA et al. alpha-Thalassemia caused by an unstable alpha-globin mutant. J Clin Invest. 1983 Mar;71(3):461-6. PMID: 6826718 Shang X et al. Rapid Targeted Next-Generation Sequencing Platform for Molecular Screening and Clinical Genotyping in Subjects with Hemoglobinopathies. EBioMedicine. 2017 Sep;23:150-159. PMID: 28865746 Zhou JY et al. First Case of a Compound Heterozygosity for Two Nondeletional a-Thalassemia mutations, Hb Constant Spring and Hb Quong Sze. Hemoglobin. 2016 Jun;40(3):210-2. PMID: 26956449

Comment:

Also known as Hb Quong Sze, Hb QS, p.L125P; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect and results in an unstable hemoglobin alpha molecule (PMID: 6826718); This variant is associated with the following publications: (PMID: 7070526, 34334003, 36059093, 32830468, 36900038, 26956449, 22589661, 28674233, 21797711, 1726096, 909565, 30275481, 19259674, 31553106, 25523870, 38123349, 24081251, 32811243, 28865746, 7515267, 23383304, SuwannasingS2016[Article], 32436451, 38112059, 32473995, 36685902, 24985555, 20144601, 32338097, 28125089, 11325652, Vijian2022[Review], 31111755, 24826791, WidyastitiNS2019[Article], 25352644, 6826718)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Alpha-Thalassemia.	Adam MP	-	2024	PMID: 20301608
Curating the gnomAD database: Report of novel variants in the globin-coding genes and bioinformatics analysis.	Scheps KG	Human mutation	2020	PMID: 31553106
LOVD-DASH: A comprehensive LOVD database coupled with diagnosis and an at-risk assessment system for hemoglobinopathies.	Zhang L	Human mutation	2019	PMID: 31286593
Pilot study of expanded carrier screening for 11 recessive diseases in China: results from 10,476 ethnically diverse couples.	Zhao S	European journal of human genetics : EJHG	2019	PMID: 30275481
Next-generation sequencing improves thalassemia carrier screening among premarital adults in a high prevalence population: the Dai nationality, China.	He J	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28125089
First Case of a Compound Heterozygosity for Two Nondeletional α-Thalassemia mutations, Hb Constant Spring and Hb Quong Sze.	Zhou JY	Hemoglobin	2016	PMID: 26956449
Identification of nondeletional α-thalassemia in a prenatal screening program by reverse dot-blot in southern China.	Li J	Hemoglobin	2015	PMID: 25523870
Phenotypic variability in a chinese family with nondeletional Hb H-Hb Quong Sze disease.	Li J	Hemoglobin	2011	PMID: 21797711
Diversity in clinical presentation of hemoglobin H disease induced by the SEA deletion and the hemoglobin Quong Sze.	Liao C	Annals of hematology	2009	PMID: 19259674
Alpha and beta thalassaemia among Chinese children in Guangxi Province, P.R. China: molecular and haematological characterization.	Liang R	British journal of haematology	1994	PMID: 7515267
Detection of the Hb Quong Sze mutation in a Chinese family by selective amplification of the alpha 2-globin gene and restriction map analysis with Msp I.	Liang S	Hemoglobin	1991	PMID: 1726096
alpha-Thalassemia caused by an unstable alpha-globin mutant.	Liebhaber SA	The Journal of clinical investigation	1983	PMID: 6826718
Globin structural mutant alpha 125Leu leads to Pro is a novel cause of alpha-thalassaemia.	Goossens M	Nature	1982	PMID: 7070526
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Text-mined citations for rs41397847 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000517.6(HBA2):c.377T>C (p.Leu126Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs41397847 ...