Submissions for variant NM_000518.5(HBB):c.*111A>G

gnomAD frequency: 0.00001  dbSNP: rs63751128

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506983	SCV000601230	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing	This variant is located in the 3-prime-untranslated region and alters the polyadenylation signal. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant was reported to likely cause the inefficient cleavage and polyadenylation of the beta globin mRNA and was associated with beta(+) thalassemia (PMID: 2375910 (1990), 1856830 (1991), 8112743 (1994), 19205970 (2009), 26418075 (2015), 26956563 (2016), 35336809 (2022)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193152	SCV001361823	pathogenic	Hemoglobinopathy	2019-08-22	criteria provided, single submitter	clinical testing	Variant summary: HBB c.*111A>G is located in the untranslated mRNA region downstream of the termination codon that lies in the 'known' polyA tail signal (AATAAA) of HBB, and mutations in this region are known to reduce the synthesis of mRNA. Therefore, this variant is expected or likely to interfere with cleavage of transcript and addition of polyA tail, leading to an elongated transcript that is unstable (PMID: 4018033). 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 31396 control chromosomes (gnomAD). c.*111A>G has been reported in the literature in multiple individuals (compound heterozygous/heterozygous and homozygous) affected with Hemoglobinopathy. Patient who was homozygous for this variant had a mild, non-transfusion dependent thalassemia phenotype (Losekoot_1991). Jankovic et al report individuals who were heterozygous for this variant had rather mild + thalassaemia, but when present in combination with other more severe types of -thalassaemia variants could result in transfusion-dependent thalassaemia major or thalassaemia intermedia (Jankovic_1990). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000506983	SCV001390934	pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing	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 is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 1856830, 2375910). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as AATGAA. ClinVar contains an entry for this variant (Variation ID: 15488). Studies have shown that this variant alters HBB gene expression (PMID: 3024968). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV004566750	SCV005051820	pathogenic	Beta-thalassemia HBB/LCRB	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000016748	SCV000037018	pathogenic	Beta-plus-thalassemia	1991-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000445654	SCV000537301	not provided	beta Thalassemia		no assertion provided	literature only
Counsyl	RCV000445654	SCV001132219	likely pathogenic	beta Thalassemia	2016-08-04	no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000445654	SCV004244267	likely pathogenic	beta Thalassemia	2023-08-02	no assertion criteria provided	clinical testing