NM_000517.6(HBA2):c.2T>G (p.Met1Arg) AND alpha Thalassemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 2, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004018237.1

Allele description [Variation Report for NM_000517.6(HBA2):c.2T>G (p.Met1Arg)]

NM_000517.6(HBA2):c.2T>G (p.Met1Arg)

Genes:

LOC106804612:hemoglobin subunit alpha 2 recombination region [Gene]
HBA2:hemoglobin subunit alpha 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000517.6(HBA2):c.2T>G (p.Met1Arg)

HGVS:

NC_000016.10:g.172914T>G
NG_000006.1:g.33777T>G
NG_046165.1:g.2653T>G
NG_059186.1:g.1264T>G
NG_059271.1:g.5068T>G
NM_000517.6:c.2T>GMANE SELECT
NM_000558.5:c.2T>GMANE SELECT
NP_000508.1:p.Met1Arg
NP_000549.1:p.Met1Arg
LRG_1225t1:c.2T>G
LRG_1240t1:c.2T>G
LRG_1225:g.1264T>G
LRG_1225p1:p.Met1Arg
LRG_1240:g.5068T>G
LRG_1240p1:p.Met1Arg
NC_000016.9:g.222913T>G

Protein change:

M1R

Molecular consequence:

NM_000517.6:c.2T>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000517.6:c.2T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_000558.5:c.2T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: alpha Thalassemia
Synonyms:: A-Thalassemia; Alpha thalassemia spectrum
Identifiers:: MONDO: MONDO:0011399; MedGen: C0002312; Orphanet: 846; OMIM: 604131

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004848908	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Feb 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848908

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Feb 2, 2023)

germline

clinical testing

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

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848908.1

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

Description

The p.Met1? (c.2T>G) in HBA2 has been previously reported in 1 individual with alpha thalessemia (Hadavi 2007 PMID 17606454). It was absent in large population studies. This variant affects the translation initiation start codon (ATG) and is therefore predicted to disrupt translation although a variety of outcomes (no protein synthesis or the activation of an upstream translation initiation codon) are possible. Other Met1? variants (c.1A>G, c.2T>C) have been reported in individuals with alpha thalessemia, and are classified as pathogenic by ClinVar submitters. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive alpha thalessemia. ACMG/AMP Criteria applied: PVS1_Moderate, PM5, PM2_Supporting, PP4. (This variant did not meet the variant calling quality criteria, and was included because it has been previously reported as a clinically significant variant.)

#	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: Sep 1, 2024

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