NM_000518.5(HBB):c.217dup (p.Ser73fs) AND not provided

Germline classification:: Pathogenic (3 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:: RCV000507557.26

Allele description [Variation Report for NM_000518.5(HBB):c.217dup (p.Ser73fs)]

NM_000518.5(HBB):c.217dup (p.Ser73fs)

Genes:

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

Variant type:

Duplication

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000518.5(HBB):c.217dup (p.Ser73fs)

Other names:

CD 71/72 (+A)

HGVS:

NC_000011.10:g.5226675dup
NC_000011.9:g.5247905dupT
NG_000007.3:g.70940_70941insA
NG_000007.3:g.70941dup
NG_042296.1:g.206dup
NG_046672.1:g.4610dup
NG_053049.1:g.2996dup
NG_059281.1:g.5397dup
NM_000518.5:c.217dupMANE SELECT
NP_000509.1:p.Ser73fs
LRG_1232t1:c.217dup
HBB:c.216_217insA
LRG_1232:g.5397dup
LRG_1232p1:p.Ser73fs
NC_000011.9:g.5247904_5247905insT
NC_000011.9:g.5247905dup
NC_000011.9:g.5247905dup
NG_000007.3:g.70940_70941insA
NM_000518.4:c.216_217insA
NM_000518.4:c.217dupA
p.Ser73Lysfs*2

Protein change:

S73fs

Links:

Genetic Testing Registry (GTR): GTR000500319; HBVAR: 869; OMIM: 141900.0328; dbSNP: rs33969853

NCBI 1000 Genomes Browser:

rs33969853

Molecular consequence:

NM_000518.5:c.217dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000601259	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Dec 30, 2020)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24369358, 19460936, 12955718, 6585831, 26956563, 26467025
SCV001410459	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23637309, 6585831, 28492532
SCV002058086	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Sep 6, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000601259

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Dec 30, 2020)

unknown

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001410459

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 4, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002058086

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Pathogenic
(Sep 6, 2022)

germline

clinical testing

Citation Link

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular basis of transfusion dependent beta-thalassemia major patients in Sabah.

Teh LK, George E, Lai MI, Tan JA, Wong L, Ismail P.

J Hum Genet. 2014 Mar;59(3):119-23. doi: 10.1038/jhg.2013.131. Epub 2013 Dec 26.

PubMed [citation]

PMID:: 24369358

Simple, efficient, and cost-effective multiplex genotyping with matrix assisted laser desorption/ionization time-of-flight mass spectrometry of hemoglobin beta gene mutations.

Thongnoppakhun W, Jiemsup S, Yongkiettrakul S, Kanjanakorn C, Limwongse C, Wilairat P, Vanasant A, Rungroj N, Yenchitsomanus PT.

J Mol Diagn. 2009 Jul;11(4):334-46. doi: 10.2353/jmoldx.2009.080151. Epub 2009 May 21.

PubMed [citation]

PMID:: 19460936
PMCID:: PMC2710711

See all PubMed Citations (8)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601259.5

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

Description

The HBB c.217dup (p.Ser73Lysfs*2) pathogenic variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant has been reported to be associated with beta(0)-thalassemia (PMIDs: 26956563 (2016), 24369358 (2014), 6585831 (1984)).

#	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 Invitae, SCV001410459.5

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

Description

This sequence change creates a premature translational stop signal (p.Ser73Lysfs*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 (rs606231217, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 6585831). This variant is also known as c.216_217insA or as an insertion of an A nucleotide between codons 71 and 72. ClinVar contains an entry for this variant (Variation ID: 15419). 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, SCV002058086.3

#	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.217dupA; p.Ser73LysfsTer2 variant (also known as Ser72fs when numbered from the mature protein or as codon 71/72 (+A); HbVar ID: 869) has been reported in individuals with beta(0) thalassemia, including in a homozygous individual with no detectable HBB mRNA (see HbVar, Cheng 1984). 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 inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the c.217dupA variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Cheng T et al. beta-Thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. Proc Natl Acad Sci U S A. 1984; 81(9):2821-5. PMID: 6585831.

#	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

Last Updated: Jun 9, 2024

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