NM_000518.4(HBB):c.430C>T (p.His144Tyr) AND not specified

Clinical significance:Likely benign (Last evaluated: May 4, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000016831.6

Allele description [Variation Report for NM_000518.4(HBB):c.430C>T (p.His144Tyr)]

NM_000518.4(HBB):c.430C>T (p.His144Tyr)

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_000518.4(HBB):c.430C>T (p.His144Tyr)
Other names:
H143Y; Hb Old Dominion/Burton-upon-Trent
HGVS:
  • NC_000011.10:g.5225612G>A
  • NG_000007.3:g.72004C>T
  • NG_046672.1:g.3547G>A
  • NG_053049.1:g.1933G>A
  • NG_059281.1:g.6460C>T
  • NM_000518.5:c.430C>TMANE SELECT
  • NP_000509.1:p.His144Tyr
  • LRG_1232t1:c.430C>T
  • HBB:c.430C>T
  • LRG_1232:g.6460C>T
  • LRG_1232p1:p.His144Tyr
  • NC_000011.9:g.5246842G>A
  • NM_000518.4:c.430C>T
Protein change:
H144Y; HIS143TYR
Links:
HBVAR: 566; OMIM: 141900.0477; dbSNP: rs33929415
NCBI 1000 Genomes Browser:
rs33929415
Molecular consequence:
  • NM_000518.5:c.430C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000037101OMIMno assertion criteria providedBenign
(Dec 12, 2017)
germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

SCV001623263Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(May 4, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A second case of Hb Bologna-St. Orsola [beta146(HC3)His-->Tyr] in an unrelated family of Anglo-Celtic origin.

Gilbert AT, Fleming PJ, Hertzberg MS.

Hemoglobin. 2000 May;24(2):139-42. No abstract available.

PubMed [citation]
PMID:
10870885

Two unrelated cases of Hb Old Dominion/Burton-upon-Trent [beta143(H21)His-->Tyr]: a rare variant causing spuriously elevated Hb A1c values.

Gilbert AT, Fleming PJ, Hertzberg MS.

Hemoglobin. 2000 May;24(2):163-4. No abstract available.

PubMed [citation]
PMID:
10870890
See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000037101.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

In investigating the nature of the unique hemoglobin variant that caused a spurious increase in glycated hemoglobin, Hb A(1c), Elder et al. (1998) found a CAC-to-TAC mutation in the HBB gene that resulted in a his143-to-tyr substitution in the beta-globin peptide. This amino acid substitution affected an important 2,3-diphosphoglycerate binding site and slightly increased the oxygen affinity of the hemoglobin variant. Despite the slight increase in oxygen affinity, the mutation was without hematologic effect, and its only clinical significance was that it coeluted with Hb A(1c) on ion-exchange chromatography and compromised the use of this analyte to monitor the treatment of diabetes mellitus. The variant was encountered in 4 unrelated persons of Irish or Scottish-Irish ancestry.

Gilbert et al. (2000) reported 2 unrelated cases of Hb Old Dominion/Burton-upon-Trent.

Plaseska-Karanfilska et al. (2000) found the same mutant hemoglobin in a 72-year-old Korean woman with type II diabetes (125853).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623263.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: HBB c.430C>T [p.His144Tyr; also known as Hb Old Dominion/Burton-upon-Trent (OD/BuT) and as legacy name p.His143Tyr] results in a conservative amino acid change located in the Globin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.430C>T has been reported in the literature in multiple individuals with diabetes mellitus who were identified as having an abnormal hemoglobin that co-elutes with hemoglobinA1c, but had no other evidence of hemoglobinopathy (e.g. Elder_1998, Gilbert_2000, Plaseska-Karanfilska_2000). These findings indicate that the variant is unlikely to be associated with hemoglobin-related disease. The only potential clinical consequence that has been observed for this variant is that it co-elutes with HbAlc on ion exchange chromatography and thereby causes a spurious increase in HbAlc, compromising the utility of this test to monitor the treatment of diabetes mellitus in individuals with the variant. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant had a slight increase in oxygen affinity that did not appear to result in a clinical impact (e.g. Elder_1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign/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

Last Updated: Nov 10, 2021

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