VCV000015459.108 - ClinVar

NM_000518.5(HBB):c.75T>A (p.Gly25=)

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.

(10)

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/Likely 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_000518.5(HBB):c.75T>A (p.Gly25=)

Variation ID: 15459 Accession: VCV000015459.108

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 5226947 (GRCh38) [ NCBI UCSC ] 11: 5248177 (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	Jan 19, 2025	Nov 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000518.5:c.75T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000509.1:p.Gly25=	synonymous
NC_000011.10:g.5226947A>T
NC_000011.9:g.5248177A>T
NG_000007.3:g.70669T>A
NG_042296.1:g.478A>T
NG_046672.1:g.4882A>T
NG_059281.1:g.5125T>A
LRG_1232:g.5125T>A
LRG_1232t1:c.75T>A	LRG_1232p1:p.Gly25=

... more HGVS ... less HGVS

Protein change

Other names

G24G
cd24T>A

Canonical SPDI

NC_000011.10:5226946:A:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00011

Links

ClinGen: CA125318 Genetic Testing Registry (GTR): GTR000500319 OMIM: 141900.0369 dbSNP: rs33951465 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.
HBB		-	-	GRCh38 GRCh37	22	1853
LOC106099062	-	-	-	GRCh38	-	871
LOC107133510	-	-	-	GRCh38	-	1802

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.
Beta-plus-thalassemia	Pathogenic (1)	no assertion criteria provided	Apr 1, 1983	RCV000016717.36
beta Thalassemia	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 20, 2019	RCV000030002.17
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 18, 2024	RCV000508672.31
Hb SS disease	Pathogenic (1)	criteria provided, single submitter	-	RCV001004354.9
Beta-thalassemia HBB/LCRB Dominant beta-thalassemia Erythrocytosis, familial, 6 Hb SS disease Heinz body anemia Hereditary persistence of fetal hemoglobin METHEMOGLOBINEMIA, BETA TYPE Malaria, susceptibility to alpha Thalassemia	Pathogenic (1)	criteria provided, single submitter	Sep 16, 2021	RCV002496383.8

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 (Nov 28, 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: SCV000603908.8 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: The HBB c.75T>A; p.Gly25Gly variant (also known as Gly24Gly when numbered from the mature protein or as codon 24 (T>A), rs33951465, HbVar ID: 805) has … (more) The HBB c.75T>A; p.Gly25Gly variant (also known as Gly24Gly when numbered from the mature protein or as codon 24 (T>A), rs33951465, HbVar ID: 805) has been reported in individuals with beta thalassemia who were homozygous for the variant or compound heterozygous with another pathogenic variant (see HbVar and ClinVar links, Gonzalez-Redondo 1988, Hattori 1989). This synonymous variant introduces a cryptic acceptor splice site and has been shown to alter splicing by reducing normal beta globin transcripts by about 75 percent (Goldsmith 1983). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Goldsmith ME et al. "Silent" nucleotide substitution in a beta+-thalassemia globin gene activates splice site in coding sequence RNA. Proc Natl Acad Sci U S A. 1983; 80(8):2318-22. PMID: 6572978 Gonzalez-Redondo JM et al. Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood. 1988; 72(3):1007-14. PMID: 2458145 Hattori Y et al. Characterization of beta-thalassemia mutations among the Japanese. Hemoglobin. 1989; 13(7-8):657-70. PMID: 2634667 (less)
pathogenic (Jun 03, 2024)	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: SCV000605847.3 First in ClinVar: Sep 30, 2017 Last updated: Jan 19, 2025	Publications: PubMed (12) PubMed: 28366028‚ 29669226‚ 23590658‚ 20737602‚ 2458145‚ 6572978‚ 2634667‚ 30626236‚ 31788855‚ 36106931‚ 37381791‚ 23055791 Comment: The HBB c.75T>A (p.Gly25=) synonymous variant has been reported in the published literature in several individuals affected with beta(+) thalassemia (PMIDs: 2458145 (1988), 2634667 (1989), … (more) The HBB c.75T>A (p.Gly25=) synonymous variant has been reported in the published literature in several individuals affected with beta(+) thalassemia (PMIDs: 2458145 (1988), 2634667 (1989), 20737602 (2010), 23590658 (2013), 28366028 (2017), 29669226 (2018), 31788855 (2020), 36106931 (2022)). This variant is reported to activate a cryptic splice donor site and significantly reduce the amount of normal HBB mRNA produced (PMID: 6572978 (1983)). The frequency of this variant in the general population, 0.0002 (5/24970 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hb SS disease Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163290.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020
Likely pathogenic (Dec 20, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Beta-thalassemia HBB/LCRB Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193989.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020	Publications: PubMed (4) PubMed: 2458145‚ 6572978‚ 6583702‚ 23590658 Comment: NM_000518.4(HBB):c.75T>A(aka G25=) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification … (more) NM_000518.4(HBB):c.75T>A(aka G25=) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the following: PMID 2458145, 6572978, 6583702 and 23590658. Classification of NM_000518.4(HBB):c.75T>A(aka G25=) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
pathogenic (Aug 18, 2011)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: curation, clinical testing	Beta Thalassemia (autosomal recessive) Affected status: yes, unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052657.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022	Publications: PubMed (8) PubMed: 6572978‚ 6188062‚ 2458145‚ 2634667‚ 6583702‚ 20737602‚ 20704537‚ 8330981 Comment: Converted during submission to Pathogenic. Observation 1: Number of individuals with the variant: 2 Observation 2: Number of individuals with the variant: 2 Observation 3: Number of individuals with the variant: 1 Observation 4: Number of individuals with the variant: 1 Observation 5: Number of individuals with the variant: 2 Observation 6: Number of individuals with the variant: 20 Observation 7: Tissue: Blood Observation 8: Tissue: Blood Observation 9: Tissue: Blood Observation 10: Tissue: Blood
Pathogenic (Sep 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Heinz body anemia Hereditary persistence of fetal hemoglobin Dominant beta-thalassemia Hb SS disease alpha Thalassemia Malaria, susceptibility to Beta-thalassemia HBB/LCRB METHEMOGLOBINEMIA, BETA TYPE Erythrocytosis, familial, 6 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002813160.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Nov 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000940351.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 2458145‚ 2634667‚ 28366028 Comment: This sequence change affects codon 25 of the HBB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 25 of the HBB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs33951465, gnomAD 0.02%). This variant has been observed in individual(s) with beta thalassaemia (PMID: 2458145, 2634667, 28366028). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 15459). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 18, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002546736.4 First in ClinVar: Jul 17, 2022 Last updated: Nov 24, 2024	Comment: Published functional studies demonstrate abnormal splicing and a decrease of normally processed beta-globin mRNA (PMID: 6572978); In silico analysis supports a deleterious effect on splicing; … (more) Published functional studies demonstrate abnormal splicing and a decrease of normally processed beta-globin mRNA (PMID: 6572978); In silico analysis supports a deleterious effect on splicing; Also known as Gly24Gly; This variant is associated with the following publications: (PMID: 25087612, 22975760, 29669226, 26044735, 2458145, 2634667, 23590658, 28366028, 6572978) (less)
Pathogenic (Apr 01, 1983)	no assertion criteria provided Method: literature only	BETA-PLUS-THALASSEMIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036987.2 First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018	Publications: PubMed (1) PubMed: 6572978 Comment on evidence: In an American black patient with beta-plus-thalassemia (613985), Goldsmith et al. (1983) found a change in codon 24 from GGT to GGA. Although silent in … (more) In an American black patient with beta-plus-thalassemia (613985), Goldsmith et al. (1983) found a change in codon 24 from GGT to GGA. Although silent in terms of changing the amino acid sequence, the mutation affected processing of mRNA. (less)
not provided (-)	no classification provided Method: literature only	beta Thalassemia Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000040715.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1426 BookShelf: NBK1426

Comment:

The HBB c.75T>A; p.Gly25Gly variant (also known as Gly24Gly when numbered from the mature protein or as codon 24 (T>A), rs33951465, HbVar ID: 805) has been reported in individuals with beta thalassemia who were homozygous for the variant or compound heterozygous with another pathogenic variant (see HbVar and ClinVar links, Gonzalez-Redondo 1988, Hattori 1989). This synonymous variant introduces a cryptic acceptor splice site and has been shown to alter splicing by reducing normal beta globin transcripts by about 75 percent (Goldsmith 1983). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Goldsmith ME et al. "Silent" nucleotide substitution in a beta+-thalassemia globin gene activates splice site in coding sequence RNA. Proc Natl Acad Sci U S A. 1983; 80(8):2318-22. PMID: 6572978 Gonzalez-Redondo JM et al. Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood. 1988; 72(3):1007-14. PMID: 2458145 Hattori Y et al. Characterization of beta-thalassemia mutations among the Japanese. Hemoglobin. 1989; 13(7-8):657-70. PMID: 2634667

Comment:

The HBB c.75T>A (p.Gly25=) synonymous variant has been reported in the published literature in several individuals affected with beta(+) thalassemia (PMIDs: 2458145 (1988), 2634667 (1989), 20737602 (2010), 23590658 (2013), 28366028 (2017), 29669226 (2018), 31788855 (2020), 36106931 (2022)). This variant is reported to activate a cryptic splice donor site and significantly reduce the amount of normal HBB mRNA produced (PMID: 6572978 (1983)). The frequency of this variant in the general population, 0.0002 (5/24970 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Comment:

NM_000518.4(HBB):c.75T>A(aka G25=) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the following: PMID 2458145, 6572978, 6583702 and 23590658. Classification of NM_000518.4(HBB):c.75T>A(aka G25=) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

This sequence change affects codon 25 of the HBB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs33951465, gnomAD 0.02%). This variant has been observed in individual(s) with beta thalassaemia (PMID: 2458145, 2634667, 28366028). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 15459). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies demonstrate abnormal splicing and a decrease of normally processed beta-globin mRNA (PMID: 6572978); In silico analysis supports a deleterious effect on splicing; Also known as Gly24Gly; This variant is associated with the following publications: (PMID: 25087612, 22975760, 29669226, 26044735, 2458145, 2634667, 23590658, 28366028, 6572978)

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
Beta-Thalassemia.	Adam MP	-	2024	PMID: 20301599
Mutation Spectrum of β-Thalassemia in Some Ethnic Groups of North Maharashtra, India.	Kumar R	Hemoglobin	2023	PMID: 37381791
Epidemiological and molecular study of hemoglobinopathies in Mauritanian patients.	Mahmoud T	Molecular genetics & genomic medicine	2022	PMID: 36106931
HbS/β+ thalassemia: Really a mild disease? A National survey from the AIEOP Sickle Cell Disease Study Group with genotype-phenotype correlation.	Notarangelo LD	European journal of haematology	2020	PMID: 31788855
β-Thalassemia Mutations in Jamaica: Geographic Variation in Small Communities.	Serjeant GR	Hemoglobin	2018	PMID: 30626236
Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia.	Thompson AA	The New England journal of medicine	2018	PMID: 29669226
Mutational Profile of Homozygous β-Thalassemia in Rio de Janeiro, Brazil.	Carrocini GCS	Hemoglobin	2017	PMID: 28366028
Prenatal and newborn screening for hemoglobinopathies.	Hoppe CC	International journal of laboratory hematology	2013	PMID: 23590658
Inherited hemoglobin disorders in an Afro-Amazonian community: Saracura.	Cardoso GL	Genetics and molecular biology	2012	PMID: 23055791
Molecular characterization of sickle cell anemia in the Northern Brazilian state of Pará.	De Lemos Cardoso G	American journal of human biology : the official journal of the Human Biology Council	2010	PMID: 20737602
ThalassoChip, an array mutation and single nucleotide polymorphism detection tool for the diagnosis of β-thalassaemia.	Shammas C	Clinical chemistry and laboratory medicine	2010	PMID: 20704537
IVS-I-1 (G-->C) in combination with -42 (C-->G) in the promoter region of the beta-globin gene in patients from Tajikistan.	Fedorov AN	Hemoglobin	1993	PMID: 8330981
Characterization of beta-thalassemia mutations among the Japanese.	Hattori Y	Hemoglobin	1989	PMID: 2634667
Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States.	Gonzalez-Redondo JM	Blood	1988	PMID: 2458145
beta-Thalassemia in American Blacks: novel mutations in the "TATA" box and an acceptor splice site.	Antonarakis SE	Proceedings of the National Academy of Sciences of the United States of America	1984	PMID: 6583702
"Silent" nucleotide substitution in a beta+-thalassemia globin gene activates splice site in coding sequence RNA.	Goldsmith ME	Proceedings of the National Academy of Sciences of the United States of America	1983	PMID: 6572978
Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes.	Treisman R	Nature	1983	PMID: 6188062
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Text-mined citations for rs33951465 ...

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 Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_000518.5(HBB):c.75T>A (p.Gly25=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs33951465 ...