Reported in unrelated patients with features of sickle cell trait; however, these patients also harbored the c.20A>T common variant (McFarlane et al., 2011; Calder et al., 2012); Also observed in patients referred for carrier screening and have normal hemoglobin testing (Lin et al., 2013; van Zwieten et al., 2014; Lou et al., 2014; Huang et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Hb New York or Hb Kaohsiung; This variant is associated with the following publications: (PMID: 24200101, 24099628, 1428942, 12403232, 28865746, 24055728, 19631632, 18432506, 1634358, 25089872, 31980563, 29626415, 36053226, 22010933, 19429541, 30837609, 29464999, 28143837, 24985555, 23346429, 23383304)
ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.341T>A (p.Val114Glu)
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.
Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(3)
Likely pathogenic(1); Uncertain significance(3)
5
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000518.5(HBB):c.341T>A (p.Val114Glu)
Variation ID: 15286 Accession: VCV000015286.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5225701 (GRCh38) [ NCBI UCSC ] 11: 5246931 (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 9, 2018 Feb 20, 2024 Oct 17, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.341T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Val114Glu missense NC_000011.10:g.5225701A>T NC_000011.9:g.5246931A>T NG_000007.3:g.71915T>A NG_046672.1:g.3636A>T NG_053049.1:g.2022A>T NG_059281.1:g.6371T>A LRG_1232:g.6371T>A LRG_1232t1:c.341T>A LRG_1232p1:p.Val114Glu - Protein change
- V114E
- Other names
-
V113E
Hb New York
Hb Kaohsiung
- Canonical SPDI
- NC_000011.10:5225700:A:T
-
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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- 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. |
|||
| HBB | - | - |
GRCh38 GRCh37 |
22 | 1835 | |
| LOC107133510 | - | - | - | GRCh38 | - | 1785 |
| LOC110006319 | - | - | - | GRCh38 | - | 984 |
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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, single submitter
|
May 27, 2021 | RCV000016516.14 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Oct 17, 2023 | RCV001284155.22 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Nov 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003929598.1
First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023 |
Comment:
Reported in unrelated patients with features of sickle cell trait; however, these patients also harbored the c.20A>T common variant (McFarlane et al., 2011; Calder et … (more)
Reported in unrelated patients with features of sickle cell trait; however, these patients also harbored the c.20A>T common variant (McFarlane et al., 2011; Calder et al., 2012); Also observed in patients referred for carrier screening and have normal hemoglobin testing (Lin et al., 2013; van Zwieten et al., 2014; Lou et al., 2014; Huang et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Hb New York or Hb Kaohsiung; This variant is associated with the following publications: (PMID: 24200101, 24099628, 1428942, 12403232, 28865746, 24055728, 19631632, 18432506, 1634358, 25089872, 31980563, 29626415, 36053226, 22010933, 19429541, 30837609, 29464999, 28143837, 24985555, 23346429, 23383304) (less)
|
|
|
Uncertain significance
(Jun 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469781.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
|
|
|
Likely pathogenic
(Oct 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001471915.6
First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024 |
Comment:
The Hb New York variant (HBB: c.341T>A; p.Val114Glu, also known as Val113Glu when numbered from the mature protein, HbVar ID: 491) is reported in the … (more)
The Hb New York variant (HBB: c.341T>A; p.Val114Glu, also known as Val113Glu when numbered from the mature protein, HbVar ID: 491) is reported in the heterozygous state in individuals with no associated hematological symptoms, and did not affect clinical symptoms when occurring in-trans with beta thalassemia or hemoglobin E, or when coinherited with alpha thalassemia trait (Chaibunruang 2018, Ranney 1967, Todd 1980, HbVar database and references therein). However, this variant is reported to contribute to a clinically significant sickling disorder in individuals who also carry the hemoglobin S allele (Calder 2012, McFarlane 2011). This variant is reported in ClinVar (Variation ID: 15286), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 114 is highly conserved, and results in a mildly unstable variant protein and reduced oxygen affinity (HbVar database and references therein). Based on available information, the Hb New York variant is considered likely pathogenic for sickling disease when found with HbS, although there is no evidence that it is disease-associated alone or in trans with a beta-thalassemia variant. References: Link to HbVar for HB New York: https://globin.bx.psu.edu/hbvar/menu.html Calder D et al. Sickle retinopathy in a person with hemoglobin s/new york disease. Case Rep Genet. 2012;2012:136582. PMID: 23346429. Chaibunruang A et al. Molecular Characteristics of Hb New York (B113(G15)Val?Glu, HBB: c.341T>A) in Thailand. Hemoglobin. 2018 Jan;42(1):11-15. PMID: 29464999. McFarlane A et al. A novel sickling hemoglobinopathy. N Engl J Med. 2011 Oct 20;365(16):1548-9. PMID: 22010933. Ranney HM et al. Haemoglobin New York. Nature. 1967 Mar 4;213(5079):876-8. PMID: 6030043. Todd D et al. Globin chain synthesis in haemoglobin New York (beta 113 replaced by glutamic acid). Br J Haematol. 1980 Dec;46(4):557-64. PMID: 7437334. (less)
|
|
|
Uncertain significance
(May 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361818.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2021 |
Comment:
Variant summary: HBB c.341T>A (p.Val114Glu) 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: HBB c.341T>A (p.Val114Glu) 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 0.00051 in 630098 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.00051 vs 0.011), allowing no conclusion about variant significance. Compound heterozygotes of c.341T>A and a beta thalassmia mutation have been reported in the literature in individuals affected with sickling disorder symptoms (McFarlane_2011). However, similar compound heterozygotes have been reported in patients without significant clinical symptoms (Zeng_1982, Lee_2008). In addition, compound heterozygotes of c.341T>A and an alpha-thalassemia allele have also been reported in patients without significant clinical symptoms (Ranney_1967, Chaibunruang_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
|
|
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Pathogenic
(Dec 01, 1980)
|
no assertion criteria provided
Method: literature only
|
HEMOGLOBIN NEW YORK
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036784.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
This variant was found in a Chinese-American family. See Ranney et al. (1967), Kendall and Pang (1980), Saenz et al. (1980), and Todd et al. … (more)
This variant was found in a Chinese-American family. See Ranney et al. (1967), Kendall and Pang (1980), Saenz et al. (1980), and Todd et al. (1980). (less)
|
Comment:
Comment:
The Hb New York variant (HBB: c.341T>A; p.Val114Glu, also known as Val113Glu when numbered from the mature protein, HbVar ID: 491) is reported in the heterozygous state in individuals with no associated hematological symptoms, and did not affect clinical symptoms when occurring in-trans with beta thalassemia or hemoglobin E, or when coinherited with alpha thalassemia trait (Chaibunruang 2018, Ranney 1967, Todd 1980, HbVar database and references therein). However, this variant is reported to contribute to a clinically significant sickling disorder in individuals who also carry the hemoglobin S allele (Calder 2012, McFarlane 2011). This variant is reported in ClinVar (Variation ID: 15286), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 114 is highly conserved, and results in a mildly unstable variant protein and reduced oxygen affinity (HbVar database and references therein). Based on available information, the Hb New York variant is considered likely pathogenic for sickling disease when found with HbS, although there is no evidence that it is disease-associated alone or in trans with a beta-thalassemia variant. References: Link to HbVar for HB New York: https://globin.bx.psu.edu/hbvar/menu.html Calder D et al. Sickle retinopathy in a person with hemoglobin s/new york disease. Case Rep Genet. 2012;2012:136582. PMID: 23346429. Chaibunruang A et al. Molecular Characteristics of Hb New York (B113(G15)Val?Glu, HBB: c.341T>A) in Thailand. Hemoglobin. 2018 Jan;42(1):11-15. PMID: 29464999. McFarlane A et al. A novel sickling hemoglobinopathy. N Engl J Med. 2011 Oct 20;365(16):1548-9. PMID: 22010933. Ranney HM et al. Haemoglobin New York. Nature. 1967 Mar 4;213(5079):876-8. PMID: 6030043. Todd D et al. Globin chain synthesis in haemoglobin New York (beta 113 replaced by glutamic acid). Br J Haematol. 1980 Dec;46(4):557-64. PMID: 7437334.
Comment:
Variant summary: HBB c.341T>A (p.Val114Glu) 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 0.00051 in 630098 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.00051 vs 0.011), allowing no conclusion about variant significance. Compound heterozygotes of c.341T>A and a beta thalassmia mutation have been reported in the literature in individuals affected with sickling disorder symptoms (McFarlane_2011). However, similar compound heterozygotes have been reported in patients without significant clinical symptoms (Zeng_1982, Lee_2008). In addition, compound heterozygotes of c.341T>A and an alpha-thalassemia allele have also been reported in patients without significant clinical symptoms (Ranney_1967, Chaibunruang_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly 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:
Reported in unrelated patients with features of sickle cell trait; however, these patients also harbored the c.20A>T common variant (McFarlane et al., 2011; Calder et al., 2012); Also observed in patients referred for carrier screening and have normal hemoglobin testing (Lin et al., 2013; van Zwieten et al., 2014; Lou et al., 2014; Huang et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Hb New York or Hb Kaohsiung; This variant is associated with the following publications: (PMID: 24200101, 24099628, 1428942, 12403232, 28865746, 24055728, 19631632, 18432506, 1634358, 25089872, 31980563, 29626415, 36053226, 22010933, 19429541, 30837609, 29464999, 28143837, 24985555, 23346429, 23383304)
Comment:
The Hb New York variant (HBB: c.341T>A; p.Val114Glu, also known as Val113Glu when numbered from the mature protein, HbVar ID: 491) is reported in the heterozygous state in individuals with no associated hematological symptoms, and did not affect clinical symptoms when occurring in-trans with beta thalassemia or hemoglobin E, or when coinherited with alpha thalassemia trait (Chaibunruang 2018, Ranney 1967, Todd 1980, HbVar database and references therein). However, this variant is reported to contribute to a clinically significant sickling disorder in individuals who also carry the hemoglobin S allele (Calder 2012, McFarlane 2011). This variant is reported in ClinVar (Variation ID: 15286), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 114 is highly conserved, and results in a mildly unstable variant protein and reduced oxygen affinity (HbVar database and references therein). Based on available information, the Hb New York variant is considered likely pathogenic for sickling disease when found with HbS, although there is no evidence that it is disease-associated alone or in trans with a beta-thalassemia variant. References: Link to HbVar for HB New York: https://globin.bx.psu.edu/hbvar/menu.html Calder D et al. Sickle retinopathy in a person with hemoglobin s/new york disease. Case Rep Genet. 2012;2012:136582. PMID: 23346429. Chaibunruang A et al. Molecular Characteristics of Hb New York (B113(G15)Val?Glu, HBB: c.341T>A) in Thailand. Hemoglobin. 2018 Jan;42(1):11-15. PMID: 29464999. McFarlane A et al. A novel sickling hemoglobinopathy. N Engl J Med. 2011 Oct 20;365(16):1548-9. PMID: 22010933. Ranney HM et al. Haemoglobin New York. Nature. 1967 Mar 4;213(5079):876-8. PMID: 6030043. Todd D et al. Globin chain synthesis in haemoglobin New York (beta 113 replaced by glutamic acid). Br J Haematol. 1980 Dec;46(4):557-64. PMID: 7437334.
Comment:
Variant summary: HBB c.341T>A (p.Val114Glu) 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 0.00051 in 630098 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.00051 vs 0.011), allowing no conclusion about variant significance. Compound heterozygotes of c.341T>A and a beta thalassmia mutation have been reported in the literature in individuals affected with sickling disorder symptoms (McFarlane_2011). However, similar compound heterozygotes have been reported in patients without significant clinical symptoms (Zeng_1982, Lee_2008). In addition, compound heterozygotes of c.341T>A and an alpha-thalassemia allele have also been reported in patients without significant clinical symptoms (Ranney_1967, Chaibunruang_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Spectrum of HBB gene mutations among 696 β-thalassemia patients and carriers in Southern Vietnam. | Xinh PT | Molecular biology reports | 2022 | PMID: 35023007 |
| Molecular characterization of thalassemia and hemoglobinopathy in Southeastern China. | Huang H | Scientific reports | 2019 | PMID: 30837609 |
| Molecular Characteristics of Hb New York [β113(G15)Val→Glu, HBB: c.341T>A] in Thailand. | Chaibunruang A | Hemoglobin | 2018 | PMID: 29464999 |
| Haematological and electrophoretic characterisation of β-thalassaemia in Yunnan province of Southwestern China. | Zhang J | BMJ open | 2017 | PMID: 28143837 |
| Hemoglobin analyses in the Netherlands reveal more than 80 different variants including six novel ones. | van Zwieten R | Hemoglobin | 2014 | PMID: 24200101 |
| Distinctive mutation spectrum of the HBB gene in an urban eastern Indian population. | Sahoo SS | Hemoglobin | 2014 | PMID: 24099628 |
| Prevalence and genetic analysis of α-thalassemia and β-thalassemia in Chongqing area of China. | Yao XY | Gene | 2013 | PMID: 24055728 |
| Hemoglobinopathy: molecular epidemiological characteristics and health effects on Hakka people in the Meizhou region, southern China. | Lin M | PloS one | 2013 | PMID: 23383304 |
| Sickle retinopathy in a person with hemoglobin s/new york disease. | Calder D | Case reports in genetics | 2012 | PMID: 23346429 |
| A novel sickling hemoglobinopathy. | McFarlane A | The New England journal of medicine | 2011 | PMID: 22010933 |
| Rapid identification of HBB gene mutations by high-resolution melting analysis. | Shih HC | Clinical biochemistry | 2009 | PMID: 19631632 |
| Double heterozygosity for Hb New York [beta 113 GTG-->GAG; VAL-->GLU] and beta degrees-thalassemia mutations manifests as a thalassemia trait. | Lee AC | Pediatric hematology and oncology | 2008 | PMID: 18432506 |
| Allele related mutation specific-polymerase chain reaction for rapid diagnosis of Hb New York (beta 113 (G15) Val-->Glu, beta(CD113 GTG-->GAG)). | Viprakasit V | Journal of the Medical Association of Thailand = Chotmaihet thangphaet | 2002 | PMID: 12403232 |
| Hb Kaohsiung or New York: a T----A substitution at codon 113 of the beta-globin chain creates an Alu I cutting site. | Chang JG | Hemoglobin | 1992 | PMID: 1634358 |
| Thermal stability and cross-linking of Hb New York [beta 113(G15)Val----Glu]. | Yang T | Hemoglobin | 1989 | PMID: 2737909 |
| Hemoglobin New York (alpha 2 beta 2 113(G15) Val leads to Glu) in China. | Zeng YT | Hemoglobin | 1982 | PMID: 7068436 |
| Identification of an abnormal hemoglobin with reduced oxygen affinity by high-performance liquid chromatography. | Sugihara J | Biochimica et biophysica acta | 1981 | PMID: 7295768 |
| Globin chain synthesis in haemoglobin New York (beta 113 replaced by glutamic acid). | Todd D | British journal of haematology | 1980 | PMID: 7437334 |
| Two cases of hemoglobin New York in Costa Rica. | Saenz GF | Hemoglobin | 1980 | PMID: 7353956 |
| Hb Vaasa or alpha2beta2 (39(C5)Gln replaced by Glu), a mildly unstable variant found in a Finnish family. | Kendall AG | Hemoglobin | 1977 | PMID: 893132 |
| Double heterozygosity for hemoglobin E and hemoglobin New York in a Thai family. | Pootrakul S | Journal of the Medical Association of Thailand = Chotmaihet thangphaet | 1971 | PMID: 5124025 |
| Hemoglobin New York in Chinese subjects in Taiwan. | Blackwell RQ | American journal of physical anthropology | 1971 | PMID: 5120550 |
| Haemoglobin New York. | Ranney HM | Nature | 1967 | PMID: 6030043 |
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Text-mined citations for rs34484056 ...
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 Nov 25, 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.