Submissions for variant NM_000518.5(HBB):c.-100G>A

gnomAD frequency: 0.00001  dbSNP: rs281864524

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	RCV001526852	SCV000697071	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: HBB c.-100G>A is located in the untranscribed region upstream of the HBB gene region. The variant allele was found at a frequency of 3.2e-05 in 31396 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.-100G>A was initially reported in compound heterozygosity with pathogenic variant c.126_129delCTTT in a Chinese boy affected with Beta Thalassemia Major (Li_2009). However, a recent study reported the variant in eight simple heterozygotes with normal hematological parameters and it two compound heterozygous individuals (with known pathogenic variants c.126_129delCTTT and c.316-197C>T) with typical hematological parameters of b-thal trait. The authors of this study concluded that c.-100G>A is likely a silent beta-thal allele (Zhao_2020). Additionally, other recent studies reported detection of the variant in a large number of carrier Chinese individuals (e.g. He_2017, Zhang_2019, Peng_2021, Tan_2021). Of particular interest is the reporting of individuals with hematological parameters indicative of carrier status who were found to be homozygous for the variant of interest (n=1) or had other known pathogenic HBB variants (c.126_129delCTTT, c.217dupA) (e.g. He_2017, Zhang_2019). These data do not allow any conclusion about variant significance. Experimental evidence evaluating an impact on protein function demonstrated the variant results in mildly reduced mRNA levels and promoter activity (Li_2009, Kircher_2019). The following publications have been ascertained in the context of this evaluation (PMID: 28125089, 31395865, 19290524, 32986258, 25526804, 33439495, 25471338, 24055728, 30809867, 32674615, 36519257, 35119136). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590577	SCV000889356	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	The HBB c.-100G>A variant has been reported in the published literature in an individual with beta-thalassemia major who was a compound heterozygote for this variant and the HBB c.126_129delCTTT (CDs 41–42 (-TTCT) variant (PMID: 19290524 (2009)). It has also been identified in carrier screens in the Chinese population (PMIDs: 33439495 (2021), 32986258 (2021), 30275481 (2019), 30809867 (2019), 28125089 (2017)). It has been described as a beta(+) variant. Functional studies suggest conflicting reports as to whether or not this variant impacts protein function (PMIDs: 31395865 (2019) and 19290524 (2009)). The frequency of this variant in the general population, 0.000032 (1/31396 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV002483568	SCV002779662	uncertain significance	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2021-10-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001272131	SCV001453791	uncertain significance	beta Thalassemia	2020-09-16	no assertion criteria provided	clinical testing