Submissions for variant NM_000517.6(HBA2):c.179G>A (p.Gly60Asp)

dbSNP: rs281864846

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507118	SCV000601207	pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	The variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant protein is described as being unstable and as having a range of mild to severe presentations of alpha thalassemia in multiple individuals with different deletional and non-deletional pathogenic variants (PMIDs: 9029003 (1997), 20642338 (2010), 27271331 (2016), 29749692 (2018), 33364739 (2020)). Based on the available information, this variant is classified as pathogenic.
Genomic Medicine Lab, University of California San Francisco	RCV001376060	SCV001573082	pathogenic	Non-immune hydrops fetalis	2020-12-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507118	SCV002048314	pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	The Hb Adana variant (HBA2: c.179G>A; p.Gly60Asp, also known as Gly59Asp when numbered from the mature protein, rs281864846, HbVar ID: 87) is reported in the literature in multiple individuals with alpha-thalassemia, Hb H disease, and hydrops fetalis usually in combination with other pathogenic variants and is often associated with a severe course of disease (see HbVar and references therein, Alauddin 2014 and 2018, Megawati 2014, Nainggolan 2010, Singh 2018). This variant is reported as highly unstable (see HbVar). This variant is reported in ClinVar (Variation ID: 439112) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.867). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Alauddin H et al. A case series of a-thalassemia intermedia due to compound heterozygosity for Hb Adana (HBA2: c179G>A (or HBA1); p.Gly60Asp) with other alpha-thalassemias in Malay families. Hemoglobin. 2014;38(4):277-81. PMID: 24829075. Alauddin H et al. A Unique Interaction of IVS-I-1 (G>A) (HBA2: c.95+1G>A) with Hb Adana (HBA2: c.179G>A) Presenting as Transfusion-Dependent alpha-Thalassemia. Hemoglobin. 2018 Jul;42(4):247-251. PMID: 30623696. Megawati D et al. Severe alpha-thalassemia intermedia due to a compound heterozygosity for the highly unstable Hb Adana (HBA2: c.179G>A) and a novel codon 24 (HBA2: c.75T>A) mutation. Hemoglobin. 2014;38(2):149-51. PMID: 24351118. Nainggolan IM et al. Hydrops fetalis associated with homozygosity for Hb Adana (alpha59(E8)Gly-->Asp (alpha2)). Hemoglobin. 2010;34(4):394-401. PMID: 20642338. Singh SA et al. Hb Adana (HBA2 or HBA1: c.179G > A) and alpha thalassemia: Genotype-phenotype correlation. Pediatr Blood Cancer. 2018 Sep;65(9):e27220. PMID: 29749692.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323574	SCV004028771	pathogenic	alpha Thalassemia	2023-07-21	criteria provided, single submitter	clinical testing	Variant summary: HBA2 c.179G>A (p.Gly60Asp) (also known as Gly59Asp/ Hb Adana ) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 131276 control chromosomes (gnomAD). c.179G>A has been reported in the literature in multiple individuals affected with alpha-thalassemia and hydrops fetalis (examples:Curuk_1993, Nainggolan_2010, Megawati_2014, and Alauddin_2014). 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: 8237999, 20642338, 24351118, 24829075). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000507118	SCV005421333	pathogenic	not provided	2024-06-04	criteria provided, single submitter	clinical testing	Reported as a common pathogenic variant among individuals of Southeast Asian background (PMID: 36900038); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(G59D) and Hb Adana; This variant is associated with the following publications: (PMID: 30025477, 29749692, 30205726, 8237999, 31286593, 26351923, 37236975, 9029003, 38112059, 27173219, 30663218, 11722414, 20642338, 24829075, 27271331, 30623696, 32860378, 33364739, 24351118, 36900038, 38694420)
OMIM	RCV001678588	SCV000043898	other	HEMOGLOBIN H HYDROPS FETALIS SYNDROME	2022-09-12	no assertion criteria provided	literature only