ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.316-70C>G (rs193922560)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV001001830 SCV000052643 likely benign not specified 2020-05-01 criteria provided, single submitter curation Variant Summary: HBB c.316-70C>G is 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 0.00076 in 31390 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.0028 vs 0.011), allowing no conclusion about variant significance. c.316-70C>G has been reported in the literature. Normal hematological values were reportedly observed in two subjects heterozygous for the variant. Furthermore, the coinheritance of c.316-70C>G in trans with the classical b0-thal allele c.93-21G>A or Hb S in two individuals did not influence or change their typical hematological and clinical features as simple b-thal carrier and sickle cell anemia carrier, respectively (Vinciguerra_2016). Additionally, a recent paper reported 15 individuals who carried c.316-70C>G in a variety of combinations with other alpha-, beta- or delta-globin gene defects and they found no influence of this sequence variant on phenotype, ultimately concluding that it is benign without thalassemic effect (Grimholt_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign (n=1) and as likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000874736 SCV001016956 benign not provided 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001830 SCV001159510 likely benign not specified 2019-03-28 criteria provided, single submitter clinical testing The HBB: c.316-70C>G variant (rs193922560), also known as IVS2-781 C>G, is reported in the literature in heterozgyous individuals without significant hematological abnormalities (Grimholt 2018, Vinciguerra 2016). While a personal communication to the HbVar database previously reported this variant in association with beta-thalassemia, no evidence to support this association was provided (see link to HbVar). Further, this variant has been observed in multiple individuals carrying additional pathogenic HBB variants and is not associated with worsening of hematological parameters (Grimholt 2018, Vinciguerra 2016). The c.316-70C>G variant is reported in ClinVar (Variation ID: 36320) and is found in the African population with an overall allele frequency of 0.26% (24/8704 alleles) in the Genome Aggregation Database. This variant is an intronic variant in a weakly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant does not alter splicing. Based on available information, this variant is considered to be likely benign. References: HbVar link to IVS2-781 C>G: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2707 Grimholt RM et al. Characterization of Two Deep Intronic Variants on the beta-Globin Gene with Inconsistent Interpretations of Clinical Significance. Hemoglobin. 2018 Mar;42(2):126-128. Vinciguerra M et al. Coinheritance of a Rare Nucleotide Substitution on the beta-Globin Gene and Other Known Mutations in the Globin Clusters: Management in Genetic Counseling. Hemoglobin. 2016 Aug;40(4):231-5.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000029988 SCV001244491 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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