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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
  • 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
  • NM_000558.1:c.2T>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004848908Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Feb 2, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024