NM_000518.5(HBB):c.25_26del (p.Lys9fs) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jan 15, 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:: RCV000506563.42

Allele description

NM_000518.5(HBB):c.25_26del (p.Lys9fs)

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.25_26del (p.Lys9fs)

Other names:

cd8-AA; CD 8 (-AA)

HGVS:

NC_000011.10:g.5226996_5226997del
NG_000007.3:g.70619_70620del
NG_042296.1:g.527_528del
NG_046672.1:g.4931_4932del
NG_059281.1:g.5075_5076del
NM_000518.5:c.25_26delMANE SELECT
NP_000509.1:p.Lys9fs
LRG_1232t1:c.25_26del
LRG_1232:g.5075_5076del
LRG_1232p1:p.Lys9fs
NC_000011.9:g.5248226_5248227del
NC_000011.9:g.5248226_5248227delTT
NM_000518.4:c.25_26delAA
p.Lys8ValfsTer13
p.Lys9Valfs*14
p.Lys9ValfsX14

Protein change:

K9fs

Links:

Genetic Testing Registry (GTR): GTR000500319; OMIM: 141900.0322; dbSNP: rs35497102

NCBI 1000 Genomes Browser:

rs35497102

Molecular consequence:

NM_000518.5:c.25_26del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000601261	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Nov 12, 2016)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 6985481, 6280057, 2430648, 3828533, 7795641, 26467025
SCV000953169	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23637309, 3828533, 25405919, 26771086, 28391758, 28492532
SCV001160183	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Oct 25, 2023)	germline	clinical testing	Citation Link,
SCV001446696	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001450319	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 8, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001961264	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2023)	germline	clinical testing	Citation Link,
SCV002818122	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 17, 2022)	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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	21	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Nonsense and frameshift mutations in beta 0-thalassemia detected in cloned beta-globin genes.

Orkin SH, Goff SC.

J Biol Chem. 1981 Oct 10;256(19):9782-4.

PubMed [citation]

PMID:: 6985481

Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster.

Orkin SH, Kazazian HH Jr, Antonarakis SE, Goff SC, Boehm CD, Sexton JP, Waber PG, Giardina PJ.

Nature. 1982 Apr 15;296(5858):627-31. No abstract available.

PubMed [citation]

PMID:: 6280057

See all PubMed Citations (12)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601261.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	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 Invitae, SCV000953169.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Lys9Valfs*14) 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 (rs35497102, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with HBB-related conditions (PMID: 3828533, 25405919, 26771086, 28391758). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 15413). 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160183.6

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

Description

The HBB c.25_26del; p.Lys9ValfsTer14 variant (also known as Lys8fsTer14 when numbered from the mature protein or as Codon 8 (-AA), rs35497102, Hbvar ID: 785) has been reported in multiple patients with beta (0) thalassemia, both in the homozygous state and in trans to another pathogenic variant (Jalilian 2017, Orkin 1981, HbVar database and references therein). This variant is found on only two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, 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/hbvar.html Jalilian M et al. The Frequency of HBB Mutations Among beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. PMID: 28391758. Orkin S et al. Nonsense and frameshift mutations in beta 0-thalassemia detected in cloned beta-globin genes. J Biol Chem. 1981; 256(19):9782-4. PMID: 6985481.

#	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 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446696.1

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

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450319.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	17	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		17	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001961264.17

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

Description

HBB: PVS1, PS4:Moderate

#	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		4	not provided	not provided	not provided

From Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital, SCV002818122.1

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

Last Updated: Jul 29, 2024

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