NM_000518.5(HBB):c.2T>G (p.Met1Arg) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 1, 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:: RCV000505904.19

Allele description [Variation Report for NM_000518.5(HBB):c.2T>G (p.Met1Arg)]

NM_000518.5(HBB):c.2T>G (p.Met1Arg)

Genes:

LOC106099062:HBB recombination 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.2T>G (p.Met1Arg)

Other names:

Init CD ATG>AGG

HGVS:

NC_000011.10:g.5227020A>C
NG_000007.3:g.70596T>G
NG_042296.1:g.551A>C
NG_046672.1:g.4955A>C
NG_059281.1:g.5052T>G
NM_000518.5:c.2T>GMANE SELECT
NP_000509.1:p.Met1Arg
LRG_1232t1:c.2T>G
LRG_1232:g.5052T>G
LRG_1232p1:p.Met1Arg
NC_000011.9:g.5248250A>C
NM_000518.4:c.2T>G
p.?
p.Met1?

Protein change:

M1R; MET1ARG

Links:

Genetic Testing Registry (GTR): GTR000500319; OMIM: 141900.0344; dbSNP: rs33941849

NCBI 1000 Genomes Browser:

rs33941849

Molecular consequence:

NM_000518.5:c.2T>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000518.5:c.2T>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000601269	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 6, 2021)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 24086942, 34474730, 33244864, 34293487, 2306523, 1517111, 1586746, 19429541, 22335963, 26715484, 27829298, 26467025
SCV000603920	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Dec 19, 2019)	germline	clinical testing	Citation Link,
SCV003439604	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 1, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12955718, 14715623, 29695942, 8144357, 20301551, 23297836, 26372199, 27117572, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000601269

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Oct 6, 2021)

unknown

clinical testing

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

SCV000603920

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Dec 19, 2019)

germline

clinical testing

Citation Link,

SCV003439604

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 1, 2023)

germline

clinical testing

PubMed (9)
[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

Hereditary hemolytic anemia in Korea from 2007 to 2011: A study by the Korean Hereditary Hemolytic Anemia Working Party of the Korean Society of Hematology.

Park ES, Jung HL, Kim HJ, Park SS, Bae SH, Shin HY, Song SH, Koh KN, Lyu CJ, Lim YT, Han DK, Hah JO.

Blood Res. 2013 Sep;48(3):211-6. doi: 10.5045/br.2013.48.3.211. Epub 2013 Sep 25.

PubMed [citation]

PMID:: 24086942
PMCID:: PMC3786282

Effectiveness of Using Mean Corpuscular Volume and Mean Corpuscular Hemoglobin for Beta-thalassemia Carrier Screening in the Guangdong Population of China.

Gu H, Wang YX, Du MX, Xu SS, Zhou BY, Li MZ.

Biomed Environ Sci. 2021 Aug 20;34(8):667-671. doi: 10.3967/bes2021.094.

PubMed [citation]

PMID:: 34474730

See all PubMed Citations (21)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601269.5

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

Description

This variant disrupts in the translation initiation codon of the HBB mRNA and is predicted to interfere with HBB protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is associated with beta-zero-thalassemia and is known to be a common Chinese beta-thalassemia pathogenic variant (PMID: 2306523 (1990), 27829298 (2016), 34474730 (2021), 34293487 (2021)). 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603920.3

#	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.2T>G; p.Met1? variant (rs33941849) is reported in the literature in individuals affected with beta(0) thalassemia (HbVar database), with no detectable expression of the beta globin protein in a patient possessing a beta(0) thalassemia variant on the other chromosome (Lam 1990). This variant is reported in ClinVar (Variation ID: 15434), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant ablates the canonical translation initiation codon, and is predicted to lead to an aberrant or absent protein. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar for c.2T>G: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=777 Lam V et al. A new single nucleotide change at the initiation codon (ATG----AGG) identified in amplified genomic DNA of a Chinese beta-thalassemic patient. Blood. 1990 75(5):1207-8.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003439604.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the HBB mRNA. The next in-frame methionine is located at codon 56. Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal recessive beta thalassemia (PMID: 12955718, 14715623, 29695942). This variant has been reported in individual(s) with autosomal dominant beta thalassemia (PMID: 8144357); however, the role of the variant in this condition is currently unclear. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HBB protein in which other variant(s) (p.Glu7Lys) have been determined to be pathogenic (PMID: 20301551, 23297836, 26372199, 27117572). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 15434). This variant is also known as CD0T>G, Initiation codon ATG‚ÜíAGG.

#	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: Oct 26, 2024

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