ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.92+6T>C (rs35724775)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417932 SCV000513211 pathogenic not provided 2021-09-27 criteria provided, single submitter clinical testing Published functional studies demonstrate that this variant results in aberrantly spliced mRNAs (Breveglieri et al., 2015); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25825561, 9163586, 9629495, 31589614, 28366028, 28670940, 28391758, 26372288, 27959697, 25856402, 26097845, 6280057, 22975760, 25525159, 21228398, 23348723)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507521 SCV000603894 pathogenic none provided 2020-08-21 criteria provided, single submitter clinical testing The HBB c.92+6T>C variant (rs35724775, ClinVar ID: 15450), also known as IVS-I-6 T>C, is reported in the literature in multiple individuals affected with beta-thalassemia (Carrocini 2017, Hussain 2017, Jalilian 2017). This variant is one of the most common beta-thalassemia alleles in Mediterranean and Middle-Eastern countries (El-Latif 2002, HbVar database and references therein). This variant disrupts the canonical splice donor site of intron 1, and functional assays show aberrant splicing of the first and second exons of HBB, leading to production of non-functional beta globin mRNA and reduction of wildtype transcripts (Breveglieri 2015). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database for IVS-I-6 (T->C): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=826 Breveglieri G et al. Generation and Characterization of a Transgenic Mouse Carrying a Functional Human beta-Globin Gene with the IVSI-6 Thalassemia Mutation. Biomed Res Int. 2015:687635. Carrocini GCS et al. Mutational Profile of Homozygous beta-Thalassemia in Rio de Janeiro, Brazil. Hemoglobin. 2017 Jan;41(1):12-15. El-Latif MA et al. The beta+-IVS-I-6 (T-->C) mutation accounts for half of the thalassemia chromosomes in the Palestinian populations of the mountain regions. Hemoglobin. 2002 Feb;26(1):33-40. Hussain A et al. Rare beta-Globin Gene Mutations in Pakistan. Hemoglobin. 2017 Mar;41(2):100-103. Jalilian M et al. The Frequency of HBB Mutations Among beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64.
Fulgent Genetics,Fulgent Genetics RCV000763252 SCV000893889 pathogenic Beta-thalassemia, dominant inclusion body type; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Susceptibility to malaria; beta Thalassemia; Methemoglobinemia, beta-globin type; Erythrocytosis 6, familial 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000415353 SCV000914518 pathogenic beta Thalassemia 2018-08-14 criteria provided, single submitter clinical testing The HBB c.92+6T>C variant, widely known as IVS-I-6, is a well-described and common cause of beta thalassemia, with the greatest frequency among Mediterranean and Middle-Eastern populations, accounting for up to 48.5 percent of disease alleles in some populations (El-Latif et al. 2002; Origa et al. 2015). Individuals who are homozygous or compound heterozygous for the c.92+6T>C variant display a range of disease phenotypes from beta thalassemia intermedia to beta thalassemia major (El-Latif et al. 2002; Origa et al. 2015). Across a selection of available literature, the c.92+6T>C variant has been identified in a homozygous state in at least 42 patients and in a compound heterozygous state with a second pathogenic variant in at least 21 individuals, with symptoms ranging from non-transfusion dependent beta thalassemia to transfusion dependent beta thalassemia major (El-Latif et al. 2002; Kakavas et al. 2006; El-Gawhary et al. 2007; Bell et al. 2011). Control data are unavailable for the c.92+6T>C variant, which is reported at a frequency of 0.00046 in the Other population of the Genome Aggregation Database. RT-PCR experiments demonstrated that the c.92+6T>C variant produces aberrantly spliced mRNA transcripts in samples derived from homozygous patients or a transgenic mouse line (TG-β-IVSI-6) (Breveglieri et al. 2015). Haplotype analysis has also shown the c.92+6T>C variant is linked to two beta-globin cluster haplotypes, Mediterranean VI and VII (El-Latif et al. 2002; Chen et al. 2015). Based on the collective evidence, the c.92+6T>C variant is classified as pathogenic for beta thalassemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000417932 SCV000963545 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein, but it affects a nucleotide within the consensus splice site of the intron. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs35724775, ExAC 0.03%). This variant has been observed in individual(s) with beta thalassemia (PMID: 7668219, 2200760, 21797703, 25856402, 28366028, 28670940, 28391758). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS-1-VI and IVS-I-6 T>C. ClinVar contains an entry for this variant (Variation ID: 15450). Studies have shown that this variant is associated with alternative splicing, which introduces a frameshift (PMID: 26097845). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004347 SCV001163282 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000415353 SCV001193939 pathogenic beta Thalassemia 2019-12-09 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.92+6T>C(aka IVS-I-6T>C) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-plus variant. Sources cited for classification include the following: PMID 7522523, 2200760, and 23321370. Classification of NM_000518.4(HBB):c.92+6T>C(aka IVS-I-6T>C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000417932 SCV001249314 pathogenic not provided 2018-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001004347 SCV001264151 uncertain significance Hb SS disease 2017-10-09 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001107024 SCV001264152 uncertain significance Fetal hemoglobin quantitative trait locus 1 2017-10-09 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001107025 SCV001264153 uncertain significance Hemoglobin E 2017-10-09 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000417932 SCV001714967 pathogenic not provided 2019-05-09 criteria provided, single submitter clinical testing
OMIM RCV000016708 SCV000036978 pathogenic Beta-plus-thalassemia 1982-04-15 no assertion criteria provided literature only
GeneReviews RCV000415353 SCV000040718 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Baylor Genetics RCV000415353 SCV000328763 pathogenic beta Thalassemia 2015-07-01 no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in HBB (NM_000518.4, c.92+6T>C) and TJP2 (NM_004817.3, c.1243delT homozygous) in one individual with reported features that include prematurity, cholestasis of the liver, mild pulmonic stenosis, chronic anemia of thalassemia, and obstructive sleep apnea. The HBB variant has been previously reported as disease-causing (PMID 20395516, 21797703, 21228398).
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000415353 SCV001244508 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation
Natera, Inc. RCV000415353 SCV001453786 pathogenic beta Thalassemia 2020-09-16 no assertion criteria provided clinical testing

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