NM_000518.5(HBB):c.316-146T>G AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 29, 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:: RCV000985748.13

Allele description [Variation Report for NM_000518.5(HBB):c.316-146T>G]

NM_000518.5(HBB):c.316-146T>G

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:

single nucleotide variant

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000518.5(HBB):c.316-146T>G

Other names:

IVS II-705 (T>G)

HGVS:

NC_000011.10:g.5225872A>C
NG_000007.3:g.71744T>G
NG_046672.1:g.3807A>C
NG_053049.1:g.2193A>C
NG_059281.1:g.6200T>G
NM_000518.5:c.316-146T>GMANE SELECT
LRG_1232t1:c.316-146T>G
LRG_1232:g.6200T>G
NC_000011.9:g.5247102A>C
NM_000518.4:c.316-146T>G

Nucleotide change:

IVS2, T-G, +705

Links:

OMIM: 141900.0366; dbSNP: rs35328027

NCBI 1000 Genomes Browser:

rs35328027

Molecular consequence:

NM_000518.5:c.316-146T>G - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000603919	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (May 10, 2022)	germline	clinical testing	Citation Link,
SCV001134226	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Aug 29, 2023)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 6280138, 20704537, 9560205, 22975760, 29251008, 30843739, 24401016, 27535164, 27258795, 20395516, 6298782, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000603919

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Pathogenic
(May 10, 2022)

germline

clinical testing

Citation Link,

SCV001134226

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Aug 29, 2023)

unknown

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

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

Five nucleotide changes in the large intervening sequence of a beta globin gene in a beta+ thalassemia patient.

Spence SE, Pergolizzi RG, Donovan-Peluso M, Kosche KA, Dobkin CS, Bank A.

Nucleic Acids Res. 1982 Feb 25;10(4):1283-94.

PubMed [citation]

PMID:: 6280138
PMCID:: PMC320525

ThalassoChip, an array mutation and single nucleotide polymorphism detection tool for the diagnosis of β-thalassaemia.

Shammas C, Papasavva T, Felekis X, Christophorou C, Roomere H, Synodinos JT, Kanavakis E, El-Khateeb M, Hamamy H, Mahmoud T, Shboul M, El Beshlawy A, Filon D, Hussein IR, Galanello R, Romeo G, Kleanthous M.

Clin Chem Lab Med. 2010 Dec;48(12):1713-8. doi: 10.1515/CCLM.2010.331. Epub 2010 Aug 13.

PubMed [citation]

PMID:: 20704537

See all PubMed Citations (12)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603919.3

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

Description

The c.316-146T>G variant (also known as IVS-II-705 (T->G), rs35328027, HbVar ID: 890) has been reported in a patient diagnosed with beta(+) thalassemia (Spence 1982). This variant is reported in ClinVar (Variation ID: 36312) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. Functional characterization of the mRNA transcript indicate that the variant causes the utilization of a cryptic splice acceptor 126 nucleotides upstream, leading to the inclusion of sequences from intron 2 of HBB (Dobkin 1983). Based on the above information, the variant is classified as pathogenic. References: HbVar link: https://globin.bx.psu.edu/hbvar/hbvar.html Dobkin C et al. Abnormal splice in a mutant human beta-globin gene not at the site of a mutation. Proc Natl Acad Sci U S A. 1983. 80(5):1184-8. PMID: 6298782. Spence S et al. Five nucleotide changes in the large intervening sequence of a beta globin gene in a beta+ thalassemia patient. Nucleic Acids Res. 1982. 10(4):1283-94. PMID: 6280138.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134226.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The HBB c.316-146T>G variant has been reported in the published literature in individuals with beta-thalassemia trait (PMID: 29251008 (2018)) and in trans with another pathogenic HBB variant in an individual with beta(+) thalassemia (PMID: 30843739 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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

Last Updated: Nov 10, 2024

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