Submissions for variant NM_000518.5(HBB):c.316-7C>A

gnomAD frequency: 0.00003  dbSNP: rs34483965

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667076	SCV000791471	likely pathogenic	beta Thalassemia	2017-05-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000150	SCV001156635	likely pathogenic	not specified	2018-09-27	criteria provided, single submitter	clinical testing	The c.[316-12T>C; 316-7C>A] complex variant is reported in the literature in multiple individuals as a very mild beta + thalassemia trait (Belisario 2015, Waye 2013), and has been found in trans with Hb S and Hb C in patients with clinical symptoms (Cross 2007, Belisario 2015, Waye 2013). The c.316-12T>C variant (rs755236703) is only observed on three alleles in the Genome Aggregation Database. The c.316-7C>A variant (rs34483965) is only observed on one allele in the Genome Aggregation Database. These are intronic variants in weakly conserved nucleotides, and computational analyses (Alamut v.2.11) predict that each variant may impact splicing by weakening the nearby canonical acceptor splice site, however, without mRNA analysis it is unclear how the combination of the two variants impact splicing. Based on available information, the c.[316-12T>C; 316-7C>A] complex variant is considered to be likely pathogenic. References: Belisario A et al. Very mild forms of Hb S/beta(+)-thalassemia in Brazilian children. Rev Bras Hematol Hemoter. 2015 37(3):198-201. Cross T et al. Sickle liver disease--an unusual presentation in a compound heterozygote for HbS and a novel beta-thalassemia mutation. Am J Hematol. 2007 82(9):852-4. Waye J et al. Mild beta(+)-thalassemia associated with two linked sequence variants: IVS-II-839 (T>C) and IVS-II-844 (C>A). Hemoglobin. 2013 37(4):378-86.
Baylor Genetics	RCV001004563	SCV001163647	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283996	SCV001469530	uncertain significance	not provided	2020-02-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001283996	SCV003439780	pathogenic	not provided	2023-08-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 551906). This variant is also known as IVS2-844C>A. This variant has been observed in individual(s) with HBB-related conditions (PMID: 17565724, 23651435, 26041423). In some individuals, it has been found in cis (on the same chromosome) with c.316-12T>C. In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change falls in intron 2 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001000150	SCV003929037	uncertain significance	not specified	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: HBB c.316-7C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251142 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.316-7C>A (legacy name IVS-II-844C>A) in isolation has been reported in the literature as a compound heterozygous genotype with the HbS variant in at-least one individual with features of Sickle liver disease (Cross_2007) and as a complex allele in cis with c.316-12T>C (legacy name IVS-II-839T>C) in individuals affected with mild Beta Thalassemia (example, Waye_2013, Belisario_2013). As the possibility of incomplete genotyping in the earlier report (Cross_2007) cannot be entirely excluded, these data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17565724, 23651435, 26041423). ClinVar contains an entry for this variant (Variation ID: 551906). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000667076	SCV002089194	likely pathogenic	beta Thalassemia	2017-07-17	no assertion criteria provided	clinical testing