NM_000518.5(HBB):c.64dup (p.Asp22fs) AND beta Thalassemia

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Apr 7, 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:: RCV000666440.3

Allele description [Variation Report for NM_000518.5(HBB):c.64dup (p.Asp22fs)]

NM_000518.5(HBB):c.64dup (p.Asp22fs)

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.64dup (p.Asp22fs)

Other names:

CD 20/21 (+G)

HGVS:

NC_000011.10:g.5226959dup
NG_000007.3:g.70658dup
NG_042296.1:g.490dup
NG_046672.1:g.4894dup
NG_059281.1:g.5114dup
NM_000518.5:c.64dupMANE SELECT
NP_000509.1:p.Asp22fs
LRG_1232t1:c.64dup
LRG_1232:g.5114dup
LRG_1232p1:p.Asp22fs
NC_000011.9:g.5248189dup
NM_000518.4:c.64dupG

Protein change:

D22fs

Links:

OMIM: 141900.0470; dbSNP: rs1554918165

NCBI 1000 Genomes Browser:

rs1554918165

Molecular consequence:

NM_000518.5:c.64dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: beta Thalassemia (BTHAL)
Synonyms:: Cooley's anemia; Erythroblastic anemia; Mediterranean anemia
Identifiers:: MONDO: MONDO:0019402; MedGen: C0005283; Orphanet: 848

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000790732	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Apr 7, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001244649	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	no assertion criteria provided	Pathogenic (Nov 25, 2019)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003929040	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 7, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000790732

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Apr 7, 2017)

unknown

clinical testing

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

Citation Link,

SCV001244649

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

no assertion criteria provided

Pathogenic
(Nov 25, 2019)

germline

curation

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

Citation Link,

SCV003929040

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 7, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Molecular basis of β-thalassemia in the western province of Saudi Arabia: identification of rare β-thalassemia mutations.

Abuzenadah AM, Hussein IM, Damanhouri GA, A-Sayes FM, Gari MA, Chaudhary AG, Zaher GF, Al-Attas A, Al-Qahtani MH.

Hemoglobin. 2011;35(4):346-57. doi: 10.3109/03630269.2011.588508.

PubMed [citation]

PMID:: 21797702

Sporadic alleles, including a novel mutation, characterize beta-thalassemia in Ashkenazi Jews.

Oppenheim A, Oron V, Filon D, Fearon CC, Rachmilewitz EA, Kazazian HH Jr, Rund D.

Hum Mutat. 1993;2(2):155-7. No abstract available.

PubMed [citation]

PMID:: 8318995

Details of each submission

From Counsyl, SCV000790732.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From The ITHANET community portal, The Cyprus Institute of Neurology and Genetics, SCV001244649.1

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003929040.1

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

Description

Variant summary: HBB c.64dupG (p.Asp22GlyfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251278 control chromosomes (gnomAD). c.64dupG has been reported in the literature in an individual reported as a Beta Thalassemia carrier (Oppenheim_1993). These report(s) do not provide unequivocal conclusions about association of the variant with Beta Thalassemia.Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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

Last Updated: Jun 9, 2024

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