VCV000015414.115 - ClinVar

NM_000518.5(HBB):c.51del (p.Lys18fs)

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.

(18)

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_000518.5(HBB):c.51del (p.Lys18fs)

Variation ID: 15414 Accession: VCV000015414.115

Type and length

Deletion, 1 bp

Location

Cytogenetic: 11p15.4 11: 5226971 (GRCh38) [ NCBI UCSC ] 11: 5248201 (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	Jun 28, 2015	Jun 2, 2024	Jan 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000518.5:c.51del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000509.1:p.Lys18fs	frameshift
NM_000518.5:c.51delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000518.4:c.51del
NC_000011.10:g.5226971del
NC_000011.9:g.5248201del
NG_000007.3:g.70645del
NG_042296.1:g.502del
NG_046672.1:g.4906del
NG_059281.1:g.5101del
LRG_1232:g.5101del
LRG_1232t1:c.51del	LRG_1232p1:p.Lys18fs

... more HGVS ... less HGVS

Protein change

K18fs

Other names

CD 16 GGC>GG-

Canonical SPDI

NC_000011.10:5226970:G:

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) 0.00000

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

HBVAR: 799 ClinGen: CA125280 Genetic Testing Registry (GTR): GTR000500319 Genetic Testing Registry (GTR): GTR000556525 OMIM: 141900.0323 dbSNP: rs35662066 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	1834
LOC106099062	-	-	-	GRCh38	-	862
LOC107133510	-	-	-	GRCh38	-	1784

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 zero thalassemia	Pathogenic (1)	no assertion criteria provided	Feb 27, 2017	RCV000016670.36
beta Thalassemia	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 17, 2019	RCV000173145.19
Hemoglobinopathy	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2016	RCV000590756.9
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 4, 2024	RCV000724162.32
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	Dec 6, 2021	RCV002482874.8
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	May 26, 2017	RCV002336087.9
Beta-thalassemia HBB/LCRB	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	-	RCV003227603.10
HBB-related disorder	Pathogenic (1)	criteria provided, single submitter	Jun 14, 2023	RCV004532367.1

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.
Pathogenic (Dec 17, 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: SCV001194166.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020	Publications: PubMed (3) PubMed: 18294253‚ 6714226‚ 21389146 Comment: NM_000518.4(HBB):c.51delC(K18Rfs2) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the … (more) NM_000518.4(HBB):c.51delC(K18Rfs2) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the following: PMID 18294253, 6714226 and 21389146. Classification of NM_000518.4(HBB):c.51delC(K18Rfs*2) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Beta-thalassemia Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001424434.1 First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020
Pathogenic (Dec 06, 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: SCV002794108.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jun 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HBB-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004116754.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The HBB c.51delC variant is predicted to result in a frameshift and premature protein termination (p.Lys18Argfs2). This variant, also referred to as Codon 16(-C), has … (more) The HBB c.51delC variant is predicted to result in a frameshift and premature protein termination (p.Lys18Argfs2). This variant, also referred to as Codon 16(-C), has been reported to be causative for beta thalassaemia (Edison et al. 2008. PubMed ID: 18294253; Kazazian et al. 1984. PubMed ID: 6714226). This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-5248200-TG-T). Frameshift variants in HBB are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Oct 12, 2022)	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: SCV002047330.2 First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024	Publications: PubMed (19) PubMed: 33829933‚ 33602051‚ 31190580‚ 32412692‚ 30489691‚ 30046479‚ 29295702‚ 11791873‚ 6714226‚ 2064964‚ 25412720‚ 22392582‚ 25135424‚ 27263053‚ 27828729‚ 26076395‚ 19254853‚ 18294253‚ 12368169 Comment: The HBB c.51del (p.Lys18Argfs2) variant (also known as Codon 16 (-C)) alters the translational reading frame of the HBB mRNA and causes the premature termination … (more) The HBB c.51del (p.Lys18Argfs2) variant (also known as Codon 16 (-C)) alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant is associated with beta(0)-thalassemia (PMIDs: 33602051(2021), 30046479 (2018), 29295702 (2018), 27828729 (2017), 26076395 (2015), and 22392582 (2012)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jan 04, 2024)	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: SCV001210575.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 23637309‚ 12368169‚ 12403498‚ 27263053 Comment: This sequence change creates a premature translational stop signal (p.Lys18Argfs2) in the HBB gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Lys18Argfs2) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs35662066, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with autosomal recessive beta-thalassemia (PMID: 12368169, 12403498, 27263053). It has also been observed to segregate with disease in related individuals. This variant is also known as "Codon 16 (-C)". ClinVar contains an entry for this variant (Variation ID: 15414). 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 10, 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: SCV000885547.4 First in ClinVar: Dec 15, 2018 Last updated: Feb 20, 2024	Comment: The Codon 16 (-C) variant (HBB: c.51delC; p.Lys18fs, also known as Lys17fs when numbered from the mature protein, rs35662066, HbVar ID: 799) is reported in … (more) The Codon 16 (-C) variant (HBB: c.51delC; p.Lys18fs, also known as Lys17fs when numbered from the mature protein, rs35662066, HbVar ID: 799) is reported in the literature in individuals with beta-thalassemia trait (Kazazian 1984, Panja 2017, Varawalla 1991, Yasmeen 2016, HbVar and references therein). This variant is reported in ClinVar (Variation ID: 15414), and is only observed on eight alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Kazazian HH Jr et al. Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 1984; 3(3):593-6. PMID: 6714226. Panja A et al. Cross-Sectional Study for the Detection of Mutations in the Beta-Globin Gene Among Patients with Hemoglobinopathies in the Bengali Population. Genet Test Mol Biomarkers. 2017; 21(1):39-45. PMID: 27828729. Varawalla N et al. The spectrum of beta-thalassaemia mutations on the Indian subcontinent: the basis for prenatal diagnosis. Br J Haematol. 1991; 78(2):242-7. PMID: 2064964. Yasmeen H et al. The molecular characterization of Beta globin gene in thalassemia patients reveals rare and a novel mutations in Pakistani population. Eur J Med Genet. 2016; 59(8):355-62. PMID: 27263053. (less)
Pathogenic (Oct 31, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hemoglobinopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697137.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (9) PubMed: 6714226‚ 18294253‚ 19254853‚ 12368169‚ 22239493‚ 22392582‚ 12779277‚ 12403498‚ 18954999 Comment: Variant summary: The HBB c.51delC (p.Lys18Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense … (more) Variant summary: The HBB c.51delC (p.Lys18Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.85dupC, c.135delC). Mutation taster predicts a damaging outcome for this variant. This variant was found in 4/121395 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). It was reported in several BTHAL patients some of whom were homologous for the variant indicating causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Feb 10, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000224234.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 6714226 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HBB Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Oct 21, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449629.1 First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020	Number of individuals with the variant: 3
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Beta-thalassemia HBB/LCRB (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003925064.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Publications: PubMed (1) PubMed: 21389146 Comment: A Heterozygous Frameshift variant c.51delC in Exon 1 of the HBB gene that results in the amino acid substitution p.Lys18fs2 was identified. The observed variant … (more) A Heterozygous Frameshift variant c.51delC in Exon 1 of the HBB gene that results in the amino acid substitution p.Lys18fs2 was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variation ID: 15414).The variant has been previously reported by Neu-Yilik G, et al., 2011. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less) Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Beta-thalassemia HBB/LCRB (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004046932.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The frameshift variant has been reported previously in homozygous and compound heterozygous state in patients affected with beta-thalassemia (Krugluger W. et al., 2002; Yasmeen H. … (more) The frameshift variant has been reported previously in homozygous and compound heterozygous state in patients affected with beta-thalassemia (Krugluger W. et al., 2002; Yasmeen H. et al., 2016). The p.Lys18ArgfsTer2 variant is reported with the allele frequency (0.003%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. This variant causes a frameshift starting with codon Lysine 18, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Lys18ArgfsTer2. The variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant , the molecular diagnosis of recessive thalassemia is not confirmed. (less) Clinical Features: Hypochromic microcytic anemia (present) , Anemia (present) , Hepatosplenomegaly (present)
Pathogenic (May 26, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002644409.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 25135424‚ 26594346‚ 6714226 Comment: The c.51delC (also known as Codon 16 del C) pathogenic mutation, located in coding exon 1 of the HBB gene, results from a deletion of … (more) The c.51delC (also known as Codon 16 del C) pathogenic mutation, located in coding exon 1 of the HBB gene, results from a deletion of one nucleotide at nucleotide position 51, causing a translational frameshift with a predicted alternate stop codon (p.K18Rfs*2). This mutation was identified in multiple Asian Indian individuals with beta thalassemia (Kazazian HH et al. EMBO J., 1984 Mar;3:593-6; Italia K et al. Br. J. Haematol., 2015 Jan;168:156-9; Rajab A et al. F1000Res, 2015 Sep;4:891). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jan 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005046492.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Number of individuals with the variant: 1
Pathogenic (Feb 27, 2017)	no assertion criteria provided Method: literature only	BETA-ZERO-THALASSEMIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036940.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 02, 2017	Publications: Kazazian, H. H., Jr. Personal (more...) Kazazian, H. H., Jr. Personal Communication. 1982. Baltimore, Md. Comment on evidence: A frameshift mutation, -C, codon 16, GGC to GG, in the HBB gene was found in Asian Indians with beta-zero-thalassemia (613985) by Kazazian et al. … (more) A frameshift mutation, -C, codon 16, GGC to GG, in the HBB gene was found in Asian Indians with beta-zero-thalassemia (613985) by Kazazian et al. (1984). (less)
Pathogenic (Feb 05, 2021)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Beta thalassemia Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV001571584.1 First in ClinVar: Apr 24, 2021 Last updated: Apr 24, 2021
Pathogenic (Nov 25, 2019)	no assertion criteria provided Method: curation	beta Thalassemia Affected status: unknown Allele origin: germline	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics Accession: SCV001244647.1 First in ClinVar: Apr 24, 2020 Last updated: Apr 24, 2020	Publications: PubMed (2) PubMed: 6714226‚ 27263053 Other databases https://ithanet.eu/db/ithagenes?… https://ithanet.eu/db/ithagenes?ithaID=75
Pathogenic (Mar 17, 2017)	no assertion criteria provided Method: clinical testing	Beta thalassemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002091600.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
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Comment:

NM_000518.4(HBB):c.51delC(K18Rfs*2) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the following: PMID 18294253, 6714226 and 21389146. Classification of NM_000518.4(HBB):c.51delC(K18Rfs*2) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Comment:

The HBB c.51delC variant is predicted to result in a frameshift and premature protein termination (p.Lys18Argfs*2). This variant, also referred to as Codon 16(-C), has been reported to be causative for beta thalassaemia (Edison et al. 2008. PubMed ID: 18294253; Kazazian et al. 1984. PubMed ID: 6714226). This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-5248200-TG-T). Frameshift variants in HBB are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

The HBB c.51del (p.Lys18Argfs*2) variant (also known as Codon 16 (-C)) alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant is associated with beta(0)-thalassemia (PMIDs: 33602051(2021), 30046479 (2018), 29295702 (2018), 27828729 (2017), 26076395 (2015), and 22392582 (2012)). Based on the available information, this variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Lys18Argfs*2) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs35662066, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with autosomal recessive beta-thalassemia (PMID: 12368169, 12403498, 27263053). It has also been observed to segregate with disease in related individuals. This variant is also known as "Codon 16 (-C)". ClinVar contains an entry for this variant (Variation ID: 15414). 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:

The Codon 16 (-C) variant (HBB: c.51delC; p.Lys18fs, also known as Lys17fs when numbered from the mature protein, rs35662066, HbVar ID: 799) is reported in the literature in individuals with beta-thalassemia trait (Kazazian 1984, Panja 2017, Varawalla 1991, Yasmeen 2016, HbVar and references therein). This variant is reported in ClinVar (Variation ID: 15414), and is only observed on eight alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Kazazian HH Jr et al. Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 1984; 3(3):593-6. PMID: 6714226. Panja A et al. Cross-Sectional Study for the Detection of Mutations in the Beta-Globin Gene Among Patients with Hemoglobinopathies in the Bengali Population. Genet Test Mol Biomarkers. 2017; 21(1):39-45. PMID: 27828729. Varawalla N et al. The spectrum of beta-thalassaemia mutations on the Indian subcontinent: the basis for prenatal diagnosis. Br J Haematol. 1991; 78(2):242-7. PMID: 2064964. Yasmeen H et al. The molecular characterization of Beta globin gene in thalassemia patients reveals rare and a novel mutations in Pakistani population. Eur J Med Genet. 2016; 59(8):355-62. PMID: 27263053.

Comment:

Variant summary: The HBB c.51delC (p.Lys18Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.85dupC, c.135delC). Mutation taster predicts a damaging outcome for this variant. This variant was found in 4/121395 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). It was reported in several BTHAL patients some of whom were homologous for the variant indicating causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

A Heterozygous Frameshift variant c.51delC in Exon 1 of the HBB gene that results in the amino acid substitution p.Lys18fs*2 was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variation ID: 15414).The variant has been previously reported by Neu-Yilik G, et al., 2011. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

Comment:

The frameshift variant has been reported previously in homozygous and compound heterozygous state in patients affected with beta-thalassemia (Krugluger W. et al., 2002; Yasmeen H. et al., 2016). The p.Lys18ArgfsTer2 variant is reported with the allele frequency (0.003%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. This variant causes a frameshift starting with codon Lysine 18, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Lys18ArgfsTer2. The variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant , the molecular diagnosis of recessive thalassemia is not confirmed.

Comment:

The c.51delC (also known as Codon 16 del C) pathogenic mutation, located in coding exon 1 of the HBB gene, results from a deletion of one nucleotide at nucleotide position 51, causing a translational frameshift with a predicted alternate stop codon (p.K18Rfs*2). This mutation was identified in multiple Asian Indian individuals with beta thalassemia (Kazazian HH et al. EMBO J., 1984 Mar;3:593-6; Italia K et al. Br. J. Haematol., 2015 Jan;168:156-9; Rajab A et al. F1000Res, 2015 Sep;4:891). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
The Changing Trends in Prenatal Diagnosis of Hemoglobinopathies in India: The Quest of a Single Center to Reduce the Burden of Disease over Three Decades.	Colah RB	Hemoglobin	2021	PMID: 33829933
Evaluation of the High Resolution Melting Approach for Detection of β-Thalassemia Gene Mutations.	Tariq A	Hemoglobin	2021	PMID: 33602051
Prevalence of globin gene modifiers encountered in fetuses during antenatal diagnosis of hemoglobinopathies.	Mehta P	International journal of laboratory hematology	2020	PMID: 32412692
Compound Heterozygote of Hb S (HBB: c.20A>T)/Hb Westdale (HBB: c.380_396delTGCAGGCTGCCTATCAG): Report of Four Cases from Odisha State, India.	Dehury S	Hemoglobin	2019	PMID: 31190580
The phenotypic and molecular diversity of hemoglobinopathies in India: A review of 15 years at a referral center.	Nadkarni AH	International journal of laboratory hematology	2019	PMID: 30489691
Impaired acylcarnitine profile in transfusion-dependent beta-thalassemia major patients in Bangladesh.	Kumar Sarker S	Journal of advanced research	2018	PMID: 30046479
High resolution melting curve analysis targeting the HBB gene mutational hot-spot offers a reliable screening approach for all common as well as most of the rare beta-globin gene mutations in Bangladesh.	Islam MT	BMC genetics	2018	PMID: 29295702
Cross-Sectional Study for the Detection of Mutations in the Beta-Globin Gene Among Patients with Hemoglobinopathies in the Bengali Population.	Panja A	Genetic testing and molecular biomarkers	2017	PMID: 27828729
The molecular characterization of Beta globin gene in thalassemia patients reveals rare and a novel mutations in Pakistani population.	Yasmeen H	European journal of medical genetics	2016	PMID: 27263053
Repository of mutations from Oman: The entry point to a national mutation database.	Rajab A	F1000Research	2015	PMID: 26594346
Molecular Basis of β-Thalassemia in the Population of the Aegean Region of Turkey: Identification of A Novel Deletion Mutation.	Ozkinay F	Hemoglobin	2015	PMID: 26076395
Transfusion-dependent thalassemia in Northern Sarawak: a molecular study to identify different genotypes in the multi-ethnic groups and the importance of genomic sequencing in unstudied populations.	Tan JA	Public health genomics	2015	PMID: 25412720
Variable phenotypes of sickle cell disease in India with the Arab-Indian haplotype.	Italia K	British journal of haematology	2015	PMID: 25135424
The molecular basis of β-thalassemia.	Thein SL	Cold Spring Harbor perspectives in medicine	2013	PMID: 23637309
Prenatal screening for β-thalassemia major reveals new and rare mutations in the Pakistani population.	Moatter T	International journal of hematology	2012	PMID: 22392582
Experience with multiplex ARMS (MARMS)-PCR for the detection of common β-thalassemia mutations in India.	Mahadik CT	Cardiovascular & hematological agents in medicinal chemistry	2012	PMID: 22239493
Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon.	Neu-Yilik G	RNA (New York, N.Y.)	2011	PMID: 21389146
Regional heterogeneity of beta-thalassemia mutations in the multi ethnic Indian population.	Colah R	Blood cells, molecules & diseases	2009	PMID: 19254853
Hydroxyurea in sickle cell disease--a study of clinico-pharmacological efficacy in the Indian haplotype.	Italia K	Blood cells, molecules & diseases	2009	PMID: 18954999
Analysis of beta globin mutations in the Indian population: presence of rare and novel mutations and region-wise heterogeneity.	Edison ES	Clinical genetics	2008	PMID: 18294253
Co-existence of the codon 16 (-C) (beta(o)) and codon 10 (C --> A) (beta+) mutations on the same beta-globin gene.	Colah RB	Hemoglobin	2003	PMID: 12779277
Identification of a compound beta-thalassemia homozygosity [codon 10 (GCC-->GCA) and codon 16 (-C)] in an Afghan family.	Krugluger W	Hemoglobin	2002	PMID: 12403498
Rare and unexpected mutations among Iranian beta-thalassemia patients and prenatal samples discovered by reverse-hybridization and DNA sequencing.	Najmabadi H	Haematologica	2002	PMID: 12368169
A multi-center study in order to further define the molecular basis of beta-thalassemia in Thailand, Pakistan, Sri Lanka, Mauritius, Syria, and India, and to develop a simple molecular diagnostic strategy by amplification refractory mutation system-polymerase chain reaction.	Old JM	Hemoglobin	2001	PMID: 11791873
The spectrum of beta-thalassaemia mutations on the Indian subcontinent: the basis for prenatal diagnosis.	Varawalla NY	British journal of haematology	1991	PMID: 2064964
Molecular characterization of seven beta-thalassemia mutations in Asian Indians.	Kazazian HH Jr	The EMBO journal	1984	PMID: 6714226
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HBB	-	-	-	-
https://ithanet.eu/db/ithagenes?ithaID=75	-	-	-	-
Kazazian, H. H., Jr. Personal Communication. 1982. Baltimore, Md.	-	-	-	-
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Text-mined citations for rs35662066 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000518.5(HBB):c.51del (p.Lys18fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs35662066 ...