Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000985730 | SCV001134203 | uncertain significance | not provided | 2019-01-08 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235439 | SCV003934597 | uncertain significance | not specified | 2023-05-02 | criteria provided, single submitter | clinical testing | Variant summary: HBA2 c.79G>A (p.Ala27Thr) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 53842 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.79G>A has been reported in the literature as a non-informative genotype (example, Lacerra_2004) or in cis with another HBA2 alteration, namely HBA2 c.391G>C (p.Ala131Pro), also known as Hb Sun Prairie (Tammadoni_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15365991, 18691171, 19373587). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant in isolation was classified as uncertain significance. |
| ARUP Laboratories, |
RCV000985730 | SCV004564995 | pathogenic | not provided | 2023-06-08 | criteria provided, single submitter | clinical testing | The Hb Southern Italy variant (HBA2: c.[79G>A; 391G>C] p.[Ala27Thr; Ala131Pro]; rsID: rs41467944, rs41529844, HbVar ID: 40, 197) is reported in the literature in the heterozygous state in individuals with mild microcythemia, and in the homozygous state in individuals with chronic hemolytic anemia (See HbVar, Cardiero 2020, Lacerra 2007, Passarello 2008). Hb Southern Italy is comprised of variants Hb Caserta (c.79G>A; p.Ala27Thr) and Hb Sun Prairie (c.391G>C; p.Ala131Pro), while carriers of Hb Sun Prairie are common (Farashi 2016), no known carriers of just Hb Caserta are known (Lacerra 2009). This variant has been shown to be highly unstable. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html. Cardiero G et al. Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy. Genes (Basel). 2020 Jul 31;11(8):870. PMID: 32751969. Farashi S et al. Point mutations which should not be overlooked in Hb H disease. Expert Rev Hematol. 2016 Jan;9(1):107-13. PMID: 26523940. Lacerra G et al. Hb Southern Italy: coexistence of two missence mutations (the Hb Sun Prairie alpha2 130 Ala > Pro and Hb Caserta alpha2 26 Ala > Thr) in a single HBA2 gene. Br J Haematol. 2009 Jun;145(6):843-4. PMID: 19344421. Lacerra G et al. Genotyping for known Mediterranean alpha-thalassemia point mutations using a multiplex amplification refractory mutation system. Haematologica. 2007 Feb;92(2):254-5. PMID: 17296579. Passarello C et al. Hb Southern Italy: coexistence of two missence mutations (the Hb Sun Prairie alpha2 130 Ala --> Pro and Hb Caserta alpha2 26 Ala --> Thr) in a single HBA2 gene. Br J Haematol. 2008 Oct;143(1):138-42. PMID: 18691171. |