Submissions for variant NM_000518.5(HBB):c.316-197C>T

gnomAD frequency: 0.00005  dbSNP: rs34451549

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029984	SCV000052639	pathogenic	Beta-thalassemia major	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000794203	SCV000603895	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	The c.316-197C>T variant (also known as IVS-II-654 C->T, rs34451549, HbVar ID:889) has been reported in the compound heterozygous state in individuals with beta (+) thalassemia intermedia and in the homozygous state in a patient with transfusion-dependent beta-thalassemia major (see link to HbVar database and references therein, Lin 2013, Wu 2017). This variant is reported as pathogenic in ClinVar (Variation ID: 15458) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant, and computational algorithms (Alamut v.2.11) predict that this variant impacts splicing by creating a novel cryptic donor splice site. Additionally, functional mRNA studies of this variant demonstrate aberrant splicing that leads to the production of a transcript that contains a premature termination codon (Cheng 1984, Huang 1994). Based on available information, this variant is considered pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Cheng T et al. beta-Thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. Proc Natl Acad Sci U S A. 1984;81(9):2821-5. PMID: 6585831 Huang SZ et al. RNA transcripts of the beta-thalassaemia allele IVS-2-654 C-->T: a small amount of normally processed beta-globin mRNA is still produced from the mutant gene. Br J Haematol. 1994 Nov;88(3):541-6. PMID: 7819066 Lin M et al. Hemoglobinopathy: molecular epidemiological characteristics and health effects on Hakka people in the Meizhou region, southern China. PLoS One. 2013;8(2):e55024. PMID: 23383304 Wu L et al. B-thalassemia caused by compound heterozygous mutations and cured by bone marrow transplantation: A case report. Mol Med Rep. 2017 Nov;16(5):6552-6557. PMID: 28901454
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794203	SCV000933597	pathogenic	not provided	2024-03-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with beta-thalassemia (PMID: 2014803, 6585831, 8435318, 29695942). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2+654C>T, IVS-II-654 (C>T). ClinVar contains an entry for this variant (Variation ID: 15458). Studies have shown that this variant results in inclusion of 73 nucleotides from intron 2 and introduces a new termination codon (PMID: 6585831). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004565	SCV001163649	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020334	SCV001193938	pathogenic	beta Thalassemia	2019-12-09	criteria provided, single submitter	clinical testing	NM_000518.4(HBB):c.316-197C>T 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 2014803, 6585381 and 8435318. Classification of NM_000518.4(HBB):c.316-197C>T 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.
GeneDx	RCV000794203	SCV001813891	pathogenic	not provided	2023-11-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as cDNA sequencing of c.316-197C>T revealed the use of a new cryptic donor site, resulting in a transcript with exons 1,2,3, and nucleotides 580-652 of intron 3; this transcript corresponds to the major species identified by blot hybridization analysis of erythroid RNA of affected patients (PMID: 6585831); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26201722, 26086873, 27469621, 26084319, 21228398, 28943547, 30275481, 22975760, 20412082, 6585831, 26290351, 26865073, 23806067, 22335963, 20642335, 27117566, 25412720, 28901454, 31124576, 10222649, 9163586, 8091935, 8161731, 2143120, 28674233, 33092414)
Revvity Omics, Revvity	RCV000794203	SCV002024969	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795421	SCV005417393	pathogenic	Beta-thalassemia HBB/LCRB		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP4+PS3
Fulgent Genetics, Fulgent Genetics	RCV005049370	SCV005684695	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2024-03-13	criteria provided, single submitter	clinical testing
OMIM	RCV000016716	SCV000036986	pathogenic	Beta zero thalassemia	1984-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000020334	SCV000040710	not provided	beta Thalassemia		no assertion provided	literature only
Natera, Inc.	RCV000020334	SCV002089196	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532371	SCV004115004	pathogenic	HBB-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The HBB c.316-197C>T variant is predicted to interfere with splicing. This variant, previously described as IVS2-654C>T, has been reported to alter splicing and be causative for beta thalassemia (Cheng et al 1984. PubMed ID: 6585831; Lin LI et al 1991. PubMed ID: 2014803; Kazazian HH Jr et al 1986. PubMed ID: 2875755 This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.