ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.316-45G>C (rs140033163)

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Total submissions: 3
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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.
Invitae RCV000874734 SCV001016954 benign not provided 2020-12-07 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

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