ClinVar Miner

Submissions for variant NM_000517.4(HBA2):c.429A>T (p.Ter143Tyr)

dbSNP: rs41412046
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508511 SCV000601217 pathogenic not provided 2023-09-19 criteria provided, single submitter clinical testing The HBA2 c.429A>T (p.*143Tyrext*31) variant, also known as Hb Pakse, disrupts the translation stop codon of the HBA2 mRNA and is predicted to cause HBA2 protein elongation. This variant has been reported in the published literature in individuals compound heterozygous with the SEA alpha-1 deletion affected with Hb H disease (PMIDs: 8193381 (1994), 11836160 (2002)) and individuals compound heterozygous with Hb Adana (PMID: 27271331 (2016)) and Hb Constant Spring affected with alpha-thalassemia (PMIDs: 21077767 (2010), 27271331 (2016), 28244614 (2018), 30615015 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508511 SCV000885544 pathogenic not provided 2023-10-05 criteria provided, single submitter clinical testing The Hb Pakse variant (HBA2: c.429A>T; p.Ter143Tyr, also known as Ter142Tyr when numbered from the mature protein, rs41412046. HbVar ID: 707) has been described in multiple individuals with alpha-thalassemia (Nguyen 2014, Pichanun 2010, Waye 1994, HbVar database). Hb Pakse is one of the most prevalent non-deletion alpha-thalassemias in Southeast Asia (Singsanan 2007). This variant is listed in ClinVar (Variation ID: 15652), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant altered the canonical termination codon, and creates elongated, unstable mRNA that results in reduced alpha-chain synthesis (Waye 1994). Based on available information, the Hb Pakse variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Nguyen et al. Hemoglobin Constant Spring is markedly high in women of an ethnic minority group in Vietnam: a community-based survey and hematologic features. Blood Cells Mol Dis. 2014; 52(4):161-5. PMID: 24368026. Pichanun et al. Molecular screening of the Hbs Constant Spring (codon 142, TAA>CAA, alpha2) and Pakse (codon 142, TAA>TAT, alpha2) mutations in Thailand. Hemoglobin. 2010; 34(6):582-6. PMID: 21077767. Singsanan et al. Molecular characterization and origins of Hb Constant Spring and Hb Pakse in Southeast Asian populations. Ann Hematol. 2007; 86(9):665-9. PMID: 17589844. Waye et al. Identification of a novel termination codon mutation (TAA-->TAT, Term-->Tyr) in the alpha 2 globin gene of a Laotian girl with hemoglobin H disease. Blood. 1994; 83(11):3418-20. PMID: 8193381.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001831576 SCV004037693 pathogenic alpha Thalassemia 2023-08-29 criteria provided, single submitter clinical testing Variant summary: HBA2 c.429A>T (p.X143TyrextX31) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. This variant is also known as Hb Pakse. Four other extensions variants disrupting this termination codon have been classified as pathogenic/likely pathogenic by ClinVar submitters. The variant was absent in 248852 control chromosomes (gnomAD). c.429A>T has been reported in the literature in multiple individuals affected with Alpha Thalassemia who were compound heterozygous with other pathogenic variants (Waye_1994, Sanchaisuriya_2002, Pornprasert_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8193381, 22881835, 12403487). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000016938 SCV000037210 pathogenic Hemoglobin H disease, nondeletional 1994-06-01 no assertion criteria provided literature only
Natera, Inc. RCV001831576 SCV002093852 pathogenic alpha Thalassemia 2017-12-29 no assertion criteria provided clinical testing

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