Submissions for variant NM_000518.5(HBB):c.316-1G>A

dbSNP: rs33952266

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668023	SCV000792565	pathogenic	beta Thalassemia	2017-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668023	SCV001370574	likely pathogenic	beta Thalassemia	2024-04-05	criteria provided, single submitter	clinical testing	Variant summary: HBB c.316-1G>A (also described in the literature as IVS-II-850G>A) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251150 control chromosomes (gnomAD). c.316-1G>A has been reported in the literature in homozygous and heterozygous individuals affected with beta-thalassemia (e.g. Al Mosawi_2020). Furthermore, beta-thal trait individuals heterozygous for the variant, were reported with a history of mild anemia and microcytosis (e.g. Curuk_1995, Knott_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting the same splice-site nucleotide (c.316-1G>C, c.316-1G>T) have been reported internally and also, in ClinVar and HGMD as pathogenic/likely pathogenic and disease-associated. The following publications have been ascertained in the context of this evaluation (PMID: 31714438, 7558878, 16466947, 9101288). ClinVar contains an entry for this variant (Variation ID: 552712). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV003558495	SCV004294093	pathogenic	not provided	2023-02-25	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 552712). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that disruption of this splice site alters HBB gene expression (PMID: 6583702). Disruption of this splice site has been observed in individuals with autosomal recessive beta-thalassemia (PMID: 2123063, 6583702). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 2 of the HBB gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
OMIM	RCV000736022	SCV000037079	pathogenic	Beta zero thalassemia	1995-05-01	no assertion criteria provided	literature only
College of Science, Al Muthanna University, Al Muthanna University	RCV000668023	SCV000804462	pathogenic	beta Thalassemia	2018-07-01	no assertion criteria provided	research
College of Science, Al Muthanna University, Al Muthanna University	RCV000736022	SCV000864065	pathogenic	Beta zero thalassemia	2018-01-01	no assertion criteria provided	research
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000668023	SCV001244415	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation