Submissions for variant NM_000517.6(HBA2):c.95+2_95+6del

dbSNP: rs41474145

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001800665	SCV001160097	pathogenic	not provided	2023-10-31	criteria provided, single submitter	clinical testing	The HBA2 c.95+2_95+6del variant (HbVar ID: 1065) is a common pathogenic alpha thalassemia variant that disrupts the canonical splice donor site of intron 1 and alters splicing (Felber 1982, Lacerra 2004, Orkin 1981, see HbVar link). Heterozygosity for this variant is predicted to result in silent carrier status. Based on the information available, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Felber BK et al. Abnormal RNA splicing causes one form of alpha thalassemia. Cell. 1982 Jul;29(3):895-902. PMID: 7151175. Lacerra G et al. Sequence variations of the alpha-globin genes: scanning of high CG content genes with DHPLC and DG-DGGE. Hum Mutat. 2004 Oct;24(4):338-49. PMID: 15365991. Orkin SH et al. Mutation in an intervening sequence splice junction in man. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5041-5. PMID: 6946451.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800665	SCV002047269	pathogenic	not provided	2020-09-30	criteria provided, single submitter	clinical testing	The c.95+2_95+6delTGAGG pathogenic variant in the alpha2-globin (HBA2) gene is the deletion of nucleotides 2 to 6 (TGAGG) of intron 1. This deletion occurs in the splice-donor site and prevents normal splicing of the alpha2-globin mRNA (see , and PMIDs: 6946451 (1981), 7151175 (1982), and 20507641 (2010)), and has been reported in individuals affected with alpha thalassemia in the published literature (PMIDs: 6946451 (1981), 7151175 (1982), 15365991 (2004), and 29115104 (2018)). An in vitro study reports no functional alpha-globin protein is synthesized from the mutant alpha2-globin allele (PMID: 7151175 (1982)).
GeneDx	RCV001800665	SCV002513024	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing	Common variant reported in individuals of Mediterranean ethnicity with HbH disease (Orkin et al., 1981; Mesbah-Amroun et al., 2008; Farra et al., 2014; de la Fuent-Gonzalo et al., 2019); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Also denoted as IVS1-5nt and alpha-Hph due to alternative nomenclature; This variant is associated with the following publications: (PMID: 6946451, 15365991, 26771086, 31025160, 7151175, 25284125, 18473243, 23215864, 31589614, 29627922)
Genetics and Molecular Pathology, SA Pathology	RCV000417225	SCV002557001	pathogenic	alpha Thalassemia	2022-12-05	criteria provided, single submitter	clinical testing	The HBA2 c.95+2_95+6del variant is classified as Pathogenic (PVS1, PS4, PP4) The HBA2 c.95+2_95+6del variant is located in a splice donor region. Computational predictions support a deleterious effect on splicing and a likely disruption of the protein reading frame and non-sense mediated decay of the resulting protein product (PVS1). This pentanucleotide HBA2:c.95+2_95+6delTGAGG deletion occurs within the 5' splice junction of the first intervening sequence, preventing normal RNA splicing. This mutation is listed on the Haemoglobin Variant Database as an alpha thalassaemia mutation (PMID: 7151175) (PS4). Present in numerous internal database patients as per alamut with consistent symptoms of alpha thalassaemia carrier. No functional studies performed. The clinical features of this case are highly specific for HBA1/2, and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4). Variants in HBA1/2 are highly specific for alpha thalassaemia. The variant has been reported in dbSNP (rs41474145) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 375746). It has been reported in HGMD (CD810004).
Fulgent Genetics, Fulgent Genetics	RCV002502452	SCV002813702	pathogenic	Heinz body anemia; alpha Thalassemia; Hemoglobin H disease; Erythrocytosis, familial, 7	2022-02-24	criteria provided, single submitter	clinical testing
GeneReviews	RCV000417225	SCV000503055	not provided	alpha Thalassemia		no assertion provided	literature only
Natera, Inc.	RCV000417225	SCV002093843	pathogenic	alpha Thalassemia	2017-08-17	no assertion criteria provided	clinical testing