Submissions for variant NM_000518.5(HBB):c.316-45G>C

gnomAD frequency: 0.00024  dbSNP: rs140033163

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590432	SCV000697117	benign	not specified	2020-07-02	criteria provided, single submitter	clinical testing	Variant summary: HBB c.316-45G>C alters a non-conserved nucleotide located at a position not widely known to affect splicing. 4/4 computational 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 0.00072 in 249984 control chromosomes, predominantly at a frequency of 0.0097 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. This frequency is close to that estimated for a pathogenic variant in HBB causing Hemoglobinopathy (0.0097 vs 0.011) suggesting this variant is possibly a benign polymorphism primarily found in the East Asian subpopulation. To our knowledge, no occurrence of c.316-45G>C in individuals affected with Hemoglobinopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Additionally, both the LOVD (locus specific database for HBB) and the IthaNet databases report this variant with a classification of benign/neutral polymorphism respectively. We have followed this variant for over three years since its initial observation at our laboratory and previously classified this variant as VUS-possibly benign due to the absence of clinical and functional evidence supporting an actionable outcome. However, the emerging consensus seem to converge on a benign outcome. Based on the evidence outlined above, the variant was re-classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000874734	SCV001016954	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590432	SCV001160652	likely benign	not specified	2019-06-29	criteria provided, single submitter	clinical testing