NM_000518.5(HBB):c.51del (p.Lys18fs) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jan 4, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000724162.32

Allele description [Variation Report for NM_000518.5(HBB):c.51del (p.Lys18fs)]

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

Genes:

LOC106099062:HBB recombination region [Gene]
HBB:hemoglobin subunit beta [Gene - OMIM - HGNC]
LOC107133510:origin of replication at HBB [Gene]

Variant type:

Deletion

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

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

Other names:

CD 16 GGC>GG-

HGVS:

NC_000011.10:g.5226971del
NG_000007.3:g.70645del
NG_042296.1:g.502del
NG_046672.1:g.4906del
NG_059281.1:g.5101del
NM_000518.5:c.51delMANE SELECT
NP_000509.1:p.Lys18fs
LRG_1232t1:c.51del
HBB:c.51delC
LRG_1232:g.5101del
LRG_1232p1:p.Lys18fs
NC_000011.9:g.5248201del
NC_000011.9:g.5248201delG
NM_000518.4:c.51del
NM_000518.4:c.51delC
NM_000518.5:c.51delCMANE SELECT
p.Lys18fs

Protein change:

K18fs

Links:

Genetic Testing Registry (GTR): GTR000500319; HBVAR: 799; OMIM: 141900.0323; dbSNP: rs35662066

NCBI 1000 Genomes Browser:

rs35662066

Molecular consequence:

NM_000518.5:c.51del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000224234	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Feb 10, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000885547	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 10, 2023)	germline	clinical testing	Citation Link,
SCV001210575	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23637309, 12368169, 12403498, 27263053, 28492532
SCV001449629	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 21, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002047330	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 12, 2022)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 33829933, 33602051, 31190580, 32412692, 30489691, 30046479, 29295702, 11791873, 6714226, 2064964, 25412720, 22392582, 25135424, 27263053, 27828729, 26076395, 19254853, 18294253, 12368169, 26467025
SCV005046492	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 19, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	3	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The molecular basis of β-thalassemia.

Thein SL.

Cold Spring Harb Perspect Med. 2013 May 1;3(5):a011700. doi: 10.1101/cshperspect.a011700. Review.

PubMed [citation]

PMID:: 23637309
PMCID:: PMC3633182

Identification of a compound beta-thalassemia homozygosity [codon 10 (GCC-->GCA) and codon 16 (-C)] in an Afghan family.

Krugluger W, Hopmeier P.

Hemoglobin. 2002 Aug;26(3):317-20. No abstract available.

PubMed [citation]

PMID:: 12403498

See all PubMed Citations (24)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000224234.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885547.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001210575.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449629.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002047330.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV005046492.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 3, 2024

ClinVar

Relating variation to medicine