Submissions for variant NM_000518.5(HBB):c.316-2A>C

dbSNP: rs33914668

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507767	SCV000601282	pathogenic	not provided	2021-11-08	criteria provided, single submitter	clinical testing	This variant (also known as IVS-II-849 (A>C)) is located in the canonical splice-acceptor site of intron 2 of the HBB gene, and disrupts normal splicing of the beta-globin mRNA. The variant is associated with beta(0)-thalassemia (PMID: 2424301 (1986)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290616	SCV001478718	pathogenic	Beta-thalassemia major	2022-03-10	criteria provided, single submitter	clinical testing	Variant summary: HBB c.316-2A>C (also known as IVS II-849A>C in the literature) 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 canonical 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. Blot hybridization analysis of RNA prepared from the erythoid cells of the patient who carried the variant and was diagnosed with HbS-beta0 thalassemia showed only RNA of normal size. The authors postulated that this may be attributed to the rapid degradation of the abnormal RNA or to the complete absence of an abnormally processed RNA (Padanilam et al, 1986). The variant was absent in 251048 control chromosomes (gnomAD). c.316-2A>C has been reported in the literature in at least an individual affected with Beta Thalassemia Major (Chouk_2004, Padanilam_1986). These data indicate that the variant is very likely to be associated with disease.Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000507767	SCV003439764	pathogenic	not provided	2022-06-14	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individuals with 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. ClinVar contains an entry for this variant (Variation ID: 21190). 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). Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID: 6583702).
OMIM	RCV000016702	SCV000036972	pathogenic	Beta zero thalassemia	1986-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000020335	SCV000040711	not provided	beta Thalassemia		no assertion provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000020335	SCV001244422	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000020335	SCV002089191	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing