NM_000518.5(HBB):c.25_26del (p.Lys9fs) AND Beta-thalassemia HBB/LCRB

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 23, 2023
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:: RCV002288500.10

Allele description [Variation Report for NM_000518.5(HBB):c.25_26del (p.Lys9fs)]

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
NM_000518.5:c.25_26delAAMANE SELECT
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)

Name:: Beta-thalassemia HBB/LCRB
Identifiers:: MONDO: MONDO:0013517; MedGen: CN322236; OMIM: 613985

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002581330	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841708	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 3828533, 25741868
SCV004041636	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Pathogenic (Oct 9, 2023)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002581330

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 27, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003841708

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2023)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004041636

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

no assertion criteria provided

Pathogenic
(Oct 9, 2023)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The molecular basis of beta-thalassemia in Lebanon: application to prenatal diagnosis.

Chehab FF, Der Kaloustian V, Khouri FP, Deeb SS, Kan YW.

Blood. 1987 Apr;69(4):1141-5.

PubMed [citation]

PMID:: 3828533

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From MGZ Medical Genetics Center, SCV002581330.1

#	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	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From 3billion, SCV003841708.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015413 / PMID: 3828533). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004041636.1

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

#	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: Oct 13, 2024

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