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NM_000518.5(HBB):c.262A>C (p.Thr88Pro) AND not specified

Germline classification:
Likely benign (2 submissions)
Last evaluated:
Jun 14, 2022
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:
RCV000508492.11

Allele description [Variation Report for NM_000518.5(HBB):c.262A>C (p.Thr88Pro)]

NM_000518.5(HBB):c.262A>C (p.Thr88Pro)

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.262A>C (p.Thr88Pro)
Other names:
T87P
HGVS:
  • NC_000011.10:g.5226630T>G
  • NG_000007.3:g.70986A>C
  • NG_042296.1:g.161T>G
  • NG_046672.1:g.4565T>G
  • NG_053049.1:g.2951T>G
  • NG_059281.1:g.5442A>C
  • NM_000518.5:c.262A>CMANE SELECT
  • NP_000509.1:p.Thr88Pro
  • LRG_1232t1:c.262A>C
  • LRG_1232:g.5442A>C
  • LRG_1232p1:p.Thr88Pro
  • NC_000011.9:g.5247860T>G
  • NM_000518.4:c.262A>C
  • P68871:p.Thr88Pro
Protein change:
T88P; THR87PRO
Links:
UniProtKB: P68871#VAR_002992; OMIM: 141900.0400; dbSNP: rs35553496
NCBI 1000 Genomes Browser:
rs35553496
Molecular consequence:
  • NM_000518.5:c.262A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000052628Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely benign
(Jun 14, 2022) 		germlineclinical testing

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

Citation Link,

SCV000603921ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)		Likely benign
(Aug 27, 2018) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Hb Valletta [beta 87(F3)Thr-->Pro] due to an A-->C substitution at codon 87 in a Calabrian family with alpha-thalassemia.

Qualtieri A, Andreoli V, Crescibene L, De Marco EV, Muglia M, Gabriele AL, Annesi G, Brancati C.

Hemoglobin. 1997 Jan;21(1):97-103. No abstract available.

PubMed [citation]
PMID:
9028827

The beta + IVS, I-NT no. 6 (T --> C) thalassaemia in heterozygotes with an associated Hb Valletta or Hb S heterozygosity in homozygotes from Malta.

Scerri CA, Abela W, Galdies R, Pizzuto M, Grech JL, Felice AE.

Br J Haematol. 1993 Apr;83(4):669-71.

PubMed [citation]
PMID:
8518184
See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052628.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: HBB c.262A>C (p.Thr88Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 252054 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant is found in 1.8% of the Maltese population (Kutlar_1991) and happens to be in tight linkage disequilibrium with the fetal Hb variant Hb F-Malta-I (HBG2 c.353A>G (p.His118Arg)). The variant has been reported in individuals in compound heterozygosity with a beta-thal causing variant (c.93+6T>C) whose hematological findings were similar to those detected in a simple heterozygous state (thalassemia trait), providing supportive evidence for a benign role (Scerri_1993). At least one publication, Kutlar_1991, reported heat stability experiments on mixtures of equal quantities of Hb A and Hb Valletta and on red cell lysates of two adult Hb Valletta heterozygotes, and showed normal stability. Another ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603921.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The HBB c.262A>C; Thr87Pro variant, also known as Hb Valletta, is reported in the literature, typically in linkage to the Hb F-Malta-I variant, in individuals affected with beta-thalassemia (Perrinello 2008, Scerri 1993) and in healthy individuals (Giambona 2006, Kutlar 1991, HbVar database and references therein). One individual with beta-thalassemia who carried the Thr87Pro variant was also homozygous for a pathogenic HBB variant (Parrinello 2008). Heat stability assays on Thr87Pro variant protein indicate this variant has normal stability (Kutlar 1991). The variant is listed ClinVar (Variation ID: 15489) and is found in the non-Finnish European population on six chromosomes in the Genome Aggregation Database. The threonine at residue 87 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on available information, the variant is considered likely benign. References: Link to HbVar database for Hb Valletta: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=417 Giambona A et al. Analysis of delta-globin gene alleles in the Sicilian population: identification of five new mutations. Haematologica. 2006 Dec;91(12):1681-4. Kutlar F et al. The linkage of Hb Valletta [alpha 2 beta 287(f3)Thr----Pro] and Hb F-Malta-I [alpha 2G gamma 2117(G19)His----Arg] in the Maltese population. Hum Genet. 1991 Apr;86(6):591-4. Perrinello G et al. Fever of unclear origin and cytopenia because of acute splenic sequestration in a young immunocompetent carrier of beta-globin mutation for Hb Valletta. Am J Med Sci. 2008 Dec;336(6):508-11. Scerri CA et al. The beta + IVS, I-NT no. 6 (T --> C) thalassaemia in heterozygotes with an associated Hb Valletta or Hb S heterozygosity in homozygotes from Malta. Br J Haematol. 1993 Apr;83(4):669-71.

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

Last Updated: Jul 15, 2024