Submissions for variant NM_000518.5(HBB):c.316-179A>C

gnomAD frequency: 0.00009  dbSNP: rs185607297

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780328	SCV000917498	uncertain significance	not specified	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: HBB c.316-179A>C is located at a non-conserved nucleotide position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. Though deep intronic positions are not widely known to affect splicing, this intronic region does harbor pathogenic HBB variants such as c.316-106C>G, c.316-146T>G and c.316-197C>T. The variant allele was found at a frequency of 0.001 in 259786 control chromosomes (gnomAD and jMorp (Tadaka_2021) databases; Yip_2004), predominantly at a frequency of 0.0039 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Beta Thalassemia (0.0039 vs 0.011), allowing no conclusion about variant significance. The variant, c.316-179A>C has been reported in the literature predominantly in East Asian individuals with beta-thalassemia trait, with mild or silent clinical phenotypes (e.g., Zhao_2016, Park_2013, Zhuang_2021, Luo_2022, Xian_2022, Ning_2023), however without strong evidence for causality. In one individual with beta-thalassemia trait and a silent clinical phenotype, the diagnosis was based on a mildly elevated HbA2 value (3.8%) that might be characteristic for beta-thalassemia carriers (Zhao_2016). However, this patient also carried another HBB variant, IVS2-5G>C (c.315+5G>C; classified as pathogenic in ClinVar) that is listed as a 'causative mutation' for beta-thalassemia by two reputable databases (Ithanet and HbVar) and could explain the observed beta-thalassemia trait phenotype. Moreover, another study reported the variant in 2/102 hematologically normal, healthy Chinese individuals (who were tested for the beta-thalassemia trait), suggesting that the variant might be a benign polymorphism (Yip_2004). 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: 24086942, 15345105, 27829298, 34690349, 35979587, 34659349, 33179747). Three ClinVar submitters (evaluation after 2014) have cited the variant as benign (n = 1), likely benign (n = 1), or uncertain significance (n = 1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000937128	SCV001082903	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000937128	SCV001469528	uncertain significance	not provided	2022-12-22	criteria provided, single submitter	clinical testing	The HBB c.316-179A>C variant, also known as IVS-II-672, has been reported in an individual with beta thalassemia trait as well as in an individual with hemolytic anemia in the published literature (PMIDs: 24086942 (2013) and 27829298 (2016)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect HBB mRNA splicing . Taking into account the available information, we are unable to determine the clinical significance of this variant.
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV003315253	SCV004015008	likely benign	beta Thalassemia	2023-01-05	no assertion criteria provided	clinical testing