Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001804165 | SCV000697128 | likely pathogenic | Hemoglobinopathy | 2024-06-05 | criteria provided, single submitter | clinical testing | Variant summary: HBB c.389C>T (p.Ala130Val; also known as Hb La Desirade) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251302 control chromosomes (gnomAD). The variant, c.389C>T, has been reported in the literature in multiple asymptomatic carriers (Alkindi_2021). To our knowledge, no homozygous occurrence was reported, however, the variant was reported together with a beta-0-thal variant in a clinically asymptomatic individual, who had elevated reticulocyte count (Merault_1986). The variant was also reported in compound heterozygosity with HbC (c.19G>A (p.Glu7Lys)), and HbE (c.79G>A (p.Glu27Lys)), in clinically asymptomatic individuals (Merault_1986, Kamseng_2017). In addition, this variant was reported in compound heterozygosity with HbS (c.20A>T (p.Glu7Val)) in several individuals who were affected with mild sickle cell anemia (Merault_1986, Alkindi_2021). These data indicate that the variant maybe associated with a milder disease phenotype, which is dependent on the variant in trans. At least one publication reported experimental evidence indicating that the variant results in a mild decrease in oxygen affinity and precipitation during the isopropanol test, suggestive of an unstable hemoglobin (Merault 1986). The following publications have been ascertained in the context of this evaluation (PMID: 20437613, 33489049, 32411010, 25677748, 26635043, 27670359, 15727901, 17932132, 3557994, 22995479, 26594346, 31553106, 37845805, 35143361). ClinVar contains an entry for this variant (Variation ID: 15245). In summary, though the variant has not been reported in homozygous form in affected individuals, however, it was reported in several individuals in compound heterozygosity with HbS, who were affected with a milder sickle cell anemia phenotype. Therefore, based on the evidence outlined above, the variant was classified as likely pathogenic. |
| ARUP Laboratories, |
RCV001284158 | SCV000883979 | likely pathogenic | not provided | 2024-07-29 | criteria provided, single submitter | clinical testing | 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. |
| Baylor Genetics | RCV001004559 | SCV001163641 | likely pathogenic | Hb SS disease | criteria provided, single submitter | clinical testing | ||
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001284158 | SCV001469785 | uncertain significance | not provided | 2023-04-27 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.00024 (6/24966 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Individuals who are heterozygous for this variant have been described as having a normal clinical presentation (PMID: 33489049 (2021)). This variant has also been observed in the compound heterozygous state in patients who had moderate to severe anemia or beta(0)-thalassemia (PMIDs: 32411010 (2020), 27670359 (2017), and 3557994 (1986)). Functional studies indicate that this variant is unstable with decreased oxygen affinity (PMID: 3557994 (1986) and 31553106 (2020)). Based on the available information, we are unable to determine the clinical significance of this variant. |
| Labcorp Genetics |
RCV001284158 | SCV003439762 | pathogenic | not provided | 2023-05-28 | criteria provided, single submitter | clinical testing | 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). |
| OMIM | RCV000016450 | SCV000036718 | other | HEMOGLOBIN LA DESIRADE | 2017-12-12 | no assertion criteria provided | literature only |