Submissions for variant NM_000518.5(HBB):c.*6C>G

dbSNP: rs34809925

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	RCV002265766	SCV000919464	pathogenic	Beta thalassemia intermedia	2022-05-20	criteria provided, single submitter	clinical testing	Variant summary: HBB c.*6C>G is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 4e-06 in 251382 control chromosomes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in HBB causing Beta Thalassemia Intermedia (0.011), allowing no conclusion about variant significance. The variant c.*6C>G (aka. +1480T>G) has been reported in the literature in multiple individuals affected with Beta Thalassemia Intermedia (e.g. Maragoudaki_1998, Jankovic_1991, Aldemir_2014). These data indicate that the variant is very likely to be associated with disease. Publications also reported in vitro experimental evidence evaluating the variant impact, and demonstrated about 20-40% reduction in mRNA levels associated with variant compared to normal beta-globin alleles (Maragoudaki_1998, Sgourou_2002), while another study showed a slightly higher (1.1 fold) levels of expression than WT (Hino_2012). One reputable database has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV002522737	SCV003439779	likely pathogenic	not provided	2022-01-20	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs34809925, gnomAD 0.0009%). This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This variant has been observed in individual(s) with autosomal recessive beta-thalassemia (PMID: 1777603, 9792288). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant does not significantly alter or has an unclear effect on HBB gene expression (PMID: 9792288, 22734587). ClinVar contains an entry for this variant (Variation ID: 393707). This variant is also known as term +6C>G or +1480C>G.
GeneReviews	RCV000445641	SCV000537299	not provided	beta Thalassemia		no assertion provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000445641	SCV001244464	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation