Submissions for variant NM_000519.4(HBD):c.82G>T (p.Ala28Ser)

gnomAD frequency: 0.00158  dbSNP: rs35152987

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000398301	SCV000330244	pathogenic	not provided	2024-09-17	criteria provided, single submitter	clinical testing	Commonly referred to as the Hb A2-Yialousa variant and has been reported numerous times in the literature and is the most common variant identified in the HBD gene in individuals from the Mediterranean area (PMID: 26754299, 23797957, 23215833, 1742490, 3401592); Published functional studies demonstrate that this variant may affect RNA splicing by strengthening an upstream cryptic splice donor site (PMID: 8900178); In silico analysis supports that this missense variant has a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12402333, 3401592, 1742490, 9054695, 23215833, 1398286, 25333069, 27884173, 20854114, 26754299, 27461962, 23797957, 30487145, 31980526, 34426522, 31688628, 31589614, 33178177, 10975439, 35930292, 37605839, 8900178)
Illumina Laboratory Services, Illumina	RCV001107109	SCV001264239	likely benign	Fetal hemoglobin quantitative trait locus 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Revvity Omics, Revvity	RCV000398301	SCV004236133	pathogenic	not provided	2023-07-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003987322	SCV004804765	likely pathogenic	Glucocorticoid-remediable aldosteronism	2024-03-17	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000398301	SCV005046494	pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing
OMIM	RCV000016221	SCV000036489	pathogenic	delta Thalassemia	2002-11-01	no assertion criteria provided	literature only
OMIM	RCV000016222	SCV000036490	other	HEMOGLOBIN A(2) YIALOUSA	2017-12-12	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000016221	SCV001142416	pathogenic	delta Thalassemia	2020-01-06	no assertion criteria provided	curation	NM_000519.3:c.82G>T in the HBD gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database. The HBD c.82G>T (p.Ala28Ser) was the most common variant found in the HBD gene in a Iran cohort with thalassemia (PMID: 26754299). In addition, De Angioletti et al. also reported that the Hb A2-Yialousa (g.82G>T) was the most prevalent (42/63 families). Functional studies indicate that A28S may affect RNA splicing by strengthening an upstream cryptic splice donor site (PMID: 1742490). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PP4; PS3.