Submissions for variant NM_000518.5(HBB):c.-140C>G

dbSNP: rs34999973

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589253	SCV000697079	uncertain significance	not specified	2024-03-21	criteria provided, single submitter	clinical testing	Variant summary: HBB c.-140C>G variant leads to a substitution in the 5' UTR conserved promoter sequence (CACCC box) at a conserved nucleotide. The transcription factor erythroid Kruppel-like factor (EKLF) specifically activates the b-globin gene by interacting with the proximal b-globin CACCC box, a known hot spot for thalassaemia mutations. It has been shown that EKLF requires both the proximal and distal CACCC boxes to maximally stimulate the b-globin gene, and thus changes to the CACCC boxes are expected to reduce HBB expression (PMID:15384985). 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 was absent in 31402 control chromosomes (gnomAD). c.-140C>G has been reported in the literature in at least 4 heterozygous carrier members of a family, with the proband being reported with anemia, microcytosis, hypochromia and elevated HbA2 (e.g. Rizo-de la Torre_2017). The variant is reported in the Ithanet database as "globin gene causative mutation". Another substitution at the same position, c.-140C>T has been classified as a pathogenic variant by our laboratory and it is reported to impair mRNA synthesis (PMIDs: 3457470 and 14555318). Furthermore, other substitutions in the same CACCC box have been classified as pathogenic by our laboratory (e.g. c.-138C>T, c.-138C>A, c.-137C>G, c.-137C>T, c.-136C>G). 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: 28603845, 33734896). ClinVar contains an entry for this variant (Variation ID: 495975). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV001078396	SCV001244601	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV001078396	SCV002091638	uncertain significance	beta Thalassemia	2021-08-19	no assertion criteria provided	clinical testing