Submissions for variant NM_000518.5(HBB):c.-75G>C

gnomAD frequency: 0.00003  dbSNP: rs63750400

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029959	SCV000052614	uncertain significance	not specified	2019-01-16	criteria provided, single submitter	clinical testing	Variant summary: The variant, HBB c.-75G>C is located 25 nucleotides upstream of the HBB gene in the untranscribed promoter region, near the conserved TATA box (nucleotide positions -32 to -26 from transcription initiation site), which is known to be involved in transcriptional regulation. The variant allele was found at a frequency of 3.2e-05 in 30964 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant c.-75G>C has been reported in the literature in one individual affected by sickle cell / beta+ thalassemia (Eng_2007). A recent publication also reported another variant affecting the same nucleotide position (i.e. c.-75G>T) as a cause of BTHAL, indicating the functional importance of this nucleotide location (Li_2015; PMID: 25657036). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508639	SCV000605835	likely pathogenic	not provided	2017-05-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894823	SCV004711598	uncertain significance	HBB-related condition	2023-11-21	criteria provided, single submitter	clinical testing	The HBB c.-75G>C variant is located in the 5' untranslated region. This variant was reported in an individual with newborn screening results consistent with Hb S/beta+ thalassemia; that patient was also found to carry an Hb S allele (Patient #1 in Eng et al. 2007. PubMed ID: 17486493). In a study of promoter function, the c.-75G>C variant was reported to exhibit similar promoter activity to wild-type (Supplementary Table 10 in Kircher et al. 2019. PubMed ID: 31395865). Other variants at this location (c.-75G>A, c.-75G>T) and numerous other variants nearby have been reported in patients with beta-thalassemia (Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-5248326-C-G). In ClinVar, it is reported with conflicting interpretations including uncertain, likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/36294/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Counsyl	RCV000984184	SCV001132220	uncertain significance	beta Thalassemia	2017-12-28	no assertion criteria provided	clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000984184	SCV001244455	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation