Submissions for variant NM_000518.5(HBB):c.-106G>C

gnomAD frequency: 0.00032  dbSNP: rs63750681

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175347	SCV000052601	uncertain significance	not specified	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: HBB c.-106G>C is located in the untranscribed region upstream of the HBB gene region. Consensus agreement among computation 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 0.00031 in 812098 control chromosomes (gnomAD database v4). This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Beta Thalassemia Intermedia (0.00031 vs 0.011), allowing no conclusion about variant significance. c.-106G>C, has been reported in the literature in a compound heterozygous patient together with a beta thalassemia major disease variant (c.92+1G>A), who had a beta thalassemia intermedia phenotype (Agouti_2008). The variant was also found in a homozygous individual, who displayed some features resembling to beta thalassemia minor, i.e. mild microcytic anemia, with low mean corpuscular hemoglobin concentration (Douzi_2015). These reports suggest that the variant might cause a milder phenotype, possibly affecting the beta gene expression. However, the variant was also reported in eight heterozygous individuals showing normal hematological values (i.e. being impossible to distinguish it from healthy, non-carrier subjects), and in at least three compound heterozygote patients carrying other globin disease variants, who showed phenotypes equivalent to patients carrying only the other alleles (Vinciguerra_2018, Belmokhtar_2022); therefore, these data suggest a benign role for the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18081706, 25754248, 21423179, 27718361, 26076395, 29157184, 35615994). ClinVar contains an entry for this variant (Variation ID: 36281). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759788	SCV000889357	uncertain significance	not provided	2020-08-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004364	SCV001163302	uncertain significance	Hb SS disease		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000759788	SCV001714973	uncertain significance	not provided	2020-01-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002290956	SCV002583271	uncertain significance	Beta-thalassemia HBB/LCRB		criteria provided, single submitter	clinical testing
GeneDx	RCV000759788	SCV005201874	uncertain significance	not provided	2024-02-22	criteria provided, single submitter	clinical testing	Observed in apparent homozygous state in a patient with moderate microcytic anemia in the literature (PMID: 25754248); Also known as -56C>G; This variant is associated with the following publications: (PMID: 35615994, 29157184, 18081706, 25754248)
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000029946	SCV001244533	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000029946	SCV002091634	uncertain significance	beta Thalassemia	2021-04-23	no assertion criteria provided	clinical testing