NM_000518.5(HBB):c.8A>C (p.His3Pro) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 1, 2019
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:: RCV000016485.6

Allele description [Variation Report for NM_000518.5(HBB):c.8A>C (p.His3Pro)]

NM_000518.5(HBB):c.8A>C (p.His3Pro)

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.8A>C (p.His3Pro)

Other names:

HBB, NH2 EXTENSION, HIS2PRO; H2P; Hb Marseille; Hb Long Island-Marseille

HGVS:

NC_000011.10:g.5227014T>G
NG_000007.3:g.70602A>C
NG_042296.1:g.545T>G
NG_046672.1:g.4949T>G
NG_059281.1:g.5058A>C
NM_000518.5:c.8A>CMANE SELECT
NP_000509.1:p.His3Pro
LRG_1232t1:c.8A>C
HBB:c.8A>C
LRG_1232:g.5058A>C
LRG_1232p1:p.His3Pro
NC_000011.9:g.5248244T>G
NM_000518.4:c.8A>C

Protein change:

H3P; HIS2PRO

Links:

HBVAR: 714; OMIM: 141900.0171; dbSNP: rs33983205

NCBI 1000 Genomes Browser:

rs33983205

Molecular consequence:

NM_000518.5:c.8A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000036752	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1989)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 6548977, 3455755, 2599888 Blouquit, Y., Lena-Russo, D., Delanoe, J., Arous, N., Bardakjian, J., Lacombe, C., Vovan, L., Orsini, A., Rosa, J., Galacteros, F. Hb Marseille beta-1(A1)NH2-met, 2(A2)his-to-3(A3)pro: first variant having a N-terminal elongated beta chain. (Abstract) Hemoglobin 9: 107-108, 1985.,
SCV001360652	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 1, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 2599888, 3455755, 3860812, 6548977, 19429541, 31152169 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000036752

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 1989)

germline

literature only

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

Blouquit, Y., Lena-Russo, D., Delanoe, J., Arous, N., Bardakjian, J., Lacombe, C., Vovan, L., Orsini, A., Rosa, J., Galacteros, F. Hb Marseille beta-1(A1)NH2-met, 2(A2)his-to-3(A3)pro: first variant having a N-terminal elongated beta chain. (Abstract) Hemoglobin 9: 107-108, 1985.,

SCV001360652

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 1, 2019)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

First report of HB Long Island-Marseille in Australia--a chance discovery.

Boi S, Hendy J, Goodall I, Gilbert A, Fleming P, Hughes WG.

Hemoglobin. 1989;13(5):515-20. No abstract available.

PubMed [citation]

PMID:: 2599888

Hemoglobin Long Island is caused by a single mutation (adenine to cytosine) resulting in a failure to cleave amino-terminal methionine.

Prchal JT, Cashman DP, Kan YW.

Proc Natl Acad Sci U S A. 1986 Jan;83(1):24-7.

PubMed [citation]

PMID:: 3455755
PMCID:: PMC322783

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000036752.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In this abnormal hemoglobin, found by isoelectric focusing in a hematologically normal though diabetic Maltese woman living in Marseille, Blouquit et al. (1984, 1985) demonstrated a double abnormality: a methionyl residue extending the NH2 terminus. This is an example of the increasing number of hemoglobin variants detected in the course of HbA1c evaluation in diabetics. Without DNA data, the authors concluded that proline in position 2 constitutes a steric impairment to the methionyl peptidase that normally eliminates the initiating methionine. The same hypothesis has been invoked to explain the apparent persistence of the initiator methionyl residue in naturally occurring proteins with a met-X sequence at the NH2-terminus, X being either a charged amino acid or a proline. Initial sequence, with abnormal residues in parentheses, equals H2N-(met)-val-(pro)-leu-thr-glu-glu-. Prchal et al. (1986) showed that the only lesion in DNA is an adenine-to-cytosine transversion in the second codon. Also see Barwick et al. (1985). Boi et al. (1989) detected this variant in Australia in the course of monitoring glycated hemoglobin (HbA1c) in diabetics. It causes a discrepancy between the HbA1c measurement and the clinical state of the diabetic patient.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360652.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: HBB c.8A>C (p.His3Pro), also known as Hb Long Island-Marseille and Hb Agrigente in the literature and variant databases, results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251140 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8A>C has been reported in the literature as an abnormal hemoglobin detected during HbA1C evaluation in diabetic patients who were otherwise hematologically normal (Barwick_1985, Blouquit_1984, Boi_1989, Wei_2019). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance until additional clinical and functional evidence becomes available.

#	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: Apr 23, 2022

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