NM_000518.5(HBB):c.389C>T (p.Ala130Val) AND not provided

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Jul 9, 2025
Review status:: criteria provided, conflicting classifications

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:: RCV001284158.25

Allele description [Variation Report for NM_000518.5(HBB):c.389C>T (p.Ala130Val)]

NM_000518.5(HBB):c.389C>T (p.Ala130Val)

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_000518.5(HBB):c.389C>T (p.Ala130Val)

Other names:

A129V

HGVS:

NC_000011.10:g.5225653G>A
NG_000007.3:g.71963C>T
NG_046672.1:g.3588G>A
NG_053049.1:g.1974G>A
NG_059281.1:g.6419C>T
NM_000518.5:c.389C>TMANE SELECT
NP_000509.1:p.Ala130Val
LRG_1232t1:c.389C>T
LRG_1232:g.6419C>T
LRG_1232p1:p.Ala130Val
NC_000011.9:g.5246883G>A
NM_000518.4:c.389C>T
P68871:p.Ala130Val

Protein change:

A130V; ALA129VAL

Links:

UniProtKB: P68871#VAR_003062; OMIM: 141900.0154; dbSNP: rs111645889

NCBI 1000 Genomes Browser:

rs111645889

Molecular consequence:

NM_000518.5:c.389C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000883979	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely pathogenic (Jul 29, 2024)	germline	clinical testing	Citation Link,
SCV001469785	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jul 9, 2025)	unknown	clinical testing	PubMed (17) [See all records that cite these PMIDs] 26594346, 20437613, 15727901, 37845805, 24652967, 30626236, 25677748, 21423179, 27670359, 3557994, 17932132, 26635043, 32411010, 35143361, 31553106, 33489049, 26467025
SCV003439762	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 28, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 33489049, 3557994, 27670359, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000883979

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Likely pathogenic
(Jul 29, 2024)

germline

clinical testing

Citation Link,

SCV001469785

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jul 9, 2025)

unknown

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

SCV003439762

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 28, 2023)

germline

clinical testing

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

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Repository of mutations from Oman: The entry point to a national mutation database.

Rajab A, Hamza N, Al Harasi S, Al Lawati F, Gibbons U, Al Alawi I, Kobus K, Hassan S, Mahir G, Al Salmi Q, Mons B, Robinson P.

F1000Res. 2015;4:891. doi: 10.12688/f1000research.6938.1.

PubMed [citation]

PMID:: 26594346
PMCID:: PMC4648203

Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE).

Al-Gazali L, Ali BR.

Hum Mutat. 2010 May;31(5):505-20. doi: 10.1002/humu.21232. Review.

PubMed [citation]

PMID:: 20437613

See all PubMed Citations (18)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883979.5

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

Description

The Hb La Desirade variant (HBB: c.389C>T; p.Ala130Val, also known as Ala129Val when numbered from the mature protein; rs111645889, HbVar ID: 531, ClinVar Variation ID: 15245) has been reported in-trans to pathogenic HBB variants (Hb C, beta0-thalassemia, Hb E) in asymptomatic individuals (Merault 1986, Kamseng 2017). However, when found in-trans with Hb S, variable presentations have been described including asymptomatic individuals and individuals with mild symptoms of sickle cell disease (e.g. recurrent mild painful episodes including chest and back pain, bilateral renal stones, splenomegaly, and hepatomegaly; Alkindi 2021). Functional study of purified Hb La Desirade indicates instability and a slight decrease in oxygen affinity (Merault 1986). This variant does not separate from hemoglobin A using standard electrophoresis (Alkindi 2021, HbVar ID: 531). This variant is observed on six chromosomes in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.818). Based on available information, the Hb La Desirade is likely pathogenic for mild sickle cell disease when found in-trans to Hb S. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Alkindi S et al. Clinical and Laboratory Features of Hemoglobin La Desirade Variant in Association with Sickle Cell and Alpha Thalassemia Genes. Mediterr J Hematol Infect Dis. 2021 Jan 1;13(1):e2021010. PMID: 33489049. Kamseng P et al. Low oxygen saturation and severe anemia in compound heterozygous Hb Louisville (beta42(CD1)Phe>Leu) and Hb La Desirade (beta129(H7)Ala>Val). Hematology. 2017;22(2):114-118. PMID: 27670359. Merault G et al. Hemoglobin La Desirade alpha A2 beta 2 129 (H7) Ala----Val: a new unstable hemoglobin. Hemoglobin. 1986;10(6):593-605. PMID: 3557994.

#	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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469785.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

The HBB c.389C>T (p.Ala130Val) variant (also known as Hb La Desirade) has been reported in the published literature in heterozygous individuals with a normal clinical presentation (HbVar (http://globin.cse.psu.edu/), PMID: 33489049 (2021)). Compound heterozygosity of this variant with Hb E (HBB c.79G>A (p.Glu27Lys)) or Hb C (HBB c.19G>A (p.Glu7Lys)) also present as clinically asymptomatic (PMIDs: 27670359 (2017), 3557994 (1986)). Individuals carrying this variant and Hb S (HBB c.20A>T (p.Glu7Val)) have clinical presentations ranging from asymptomatic to mild microcytic anemia (PMIDs: 33489049 (2021), 3557994 (1986)). Functional studies indicate that this variant is unstable with decreased oxygen affinity (PMIDs: 3557994 (1986), 31553106 (2020)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003439762.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HBB protein function. ClinVar contains an entry for this variant (Variation ID: 15245). This variant is also known as Hb La Desirade. This missense change has been observed in individual(s) with sickle cell anemia (PMID: 33489049). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive beta thalassemia (PMID: 3557994, 27670359); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs111645889, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 130 of the HBB protein (p.Ala130Val).

#	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: Dec 7, 2025

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