ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.*111A>G (rs63751128)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506983 SCV000601230 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2019-07-03 criteria provided, single submitter clinical testing This sequence change falls into the 3' UTR of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. This variant has been observed in individual(s) beta thalassemia (PMID: 1856830, 2375910). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as AATGAA in the literature. ClinVar contains an entry for this variant (Variation ID: 15488). Experimental studies have shown that this variant disrupts splicing (PMID: 3024968). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016748 SCV000037018 pathogenic Beta-plus-thalassemia 1991-04-01 no assertion criteria provided literature only
GeneReviews RCV000445654 SCV000537301 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Counsyl RCV000445654 SCV001132219 likely pathogenic beta Thalassemia 2016-08-04 no assertion criteria provided clinical testing

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