NM_000518.5(HBB):c.323dup (p.Asn109fs) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 13, 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:: RCV000506185.25

Allele description [Variation Report for NM_000518.5(HBB):c.323dup (p.Asn109fs)]

NM_000518.5(HBB):c.323dup (p.Asn109fs)

Genes:

LOC110006319:beta-globin gene 3' regulatory 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.323dup (p.Asn109fs)

Other names:

CD 106/107 (+G)

HGVS:

NC_000011.10:g.5225721dup
NG_000007.3:g.71897dup
NG_046672.1:g.3656dup
NG_053049.1:g.2042dup
NG_059281.1:g.6353dup
NM_000518.5:c.323dupMANE SELECT
NP_000509.1:p.Asn109fs
LRG_1232t1:c.323dup
HBB:c.321_322insG
LRG_1232:g.6353dup
LRG_1232p1:p.Asn109fs
NC_000011.9:g.5246948_5246949insC
NC_000011.9:g.5246951dup
NM_000518.4:c.323dup
NM_000518.4:c.323dupG
p.Asn109Glnfs*32

Protein change:

N109fs

Links:

HBVAR: 945; OMIM: 141900.0329; dbSNP: rs35225141

NCBI 1000 Genomes Browser:

rs35225141

Molecular consequence:

NM_000518.5:c.323dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000601289	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 12, 2022)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1728311, 23590658, 21119755, 19254853, 18294253, 3683554, 26467025
SCV001384504	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 22, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 3683554, 8535446, 31190580, 28492532
SCV002048071	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Oct 13, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000601289

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Oct 12, 2022)

unknown

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001384504

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 22, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002048071

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Pathogenic
(Oct 13, 2023)

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

Mean corpuscular volume of heterozygotes for beta-thalassemia correlates with the severity of mutations.

Rund D, Filon D, Strauss N, Rachmilewitz EA, Oppenheim A.

Blood. 1992 Jan 1;79(1):238-43.

PubMed [citation]

PMID:: 1728311

Prenatal and newborn screening for hemoglobinopathies.

Hoppe CC.

Int J Lab Hematol. 2013 Jun;35(3):297-305. doi: 10.1111/ijlh.12076. Review.

PubMed [citation]

PMID:: 23590658

See all PubMed Citations (10)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601289.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The HBB c.323dup (p.Asn109Glnfs*32) frameshift variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. In the published literature, the variant has been reported in individuals with beta-thalassemia (PMID: 3683554 (1987), 23590658 (2013)). 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001384504.5

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

Description

This sequence change creates a premature translational stop signal (p.Asn109Glnfs*32) in the HBB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acid(s) of the HBB protein. This variant is present in population databases (rs606231216, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with HBB-related conditions (PMID: 3683554). ClinVar contains an entry for this variant (Variation ID: 439153). This variant disrupts a region of the HBB protein in which other variant(s) (p.Val127Glufs*8) have been determined to be pathogenic (PMID: 8535446, 31190580). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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, SCV002048071.4

#	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.323dupG; p.Asn109GlnfsTer32 variant (rs35225141, HbVar ID: 945), also known as c.321_322insG and Codon 106/107 (+G), has been reported in individuals with beta(0) thalassemia (Hoppe 2013), and found with another pathogenic HBB variant (Wong 1987). This variant is reported as pathogenic in ClinVar (Variation ID: 439153). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by duplicating 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 Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. PMID: 23590658. Wong C et al. Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987 Nov 26-Dec 2;330(6146):384-6. PMID: 3683554.

#	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: Nov 3, 2024

ClinVar

Relating variation to medicine