Submissions for variant NC_000011.10:g.5227172G>A

gnomAD frequency: 0.00003  dbSNP: rs63751208

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169081	SCV000220255	pathogenic	beta Thalassemia	2014-04-17	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169081	SCV000697087	pathogenic	beta Thalassemia	2017-08-07	criteria provided, single submitter	clinical testing	Variant summary: c.-151C>T affects a non-conserved nucleotide in the promoter of HBB gene. Mutation Taster predicts a damaging outcome for this variant. This prediction was confirmed by a CAT promoter activity assay showing that this variant decreased promoter activity by 70% (Gonzalez-Redondo_1989). This variant was found in 1/31016 control chromosomes at a frequency of 0.0000322, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant is a well-known pathogenic HBB variant and has been reported in more than thirty unrelated patients with b-thalassemia intermedia. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820736	SCV000961462	pathogenic	not provided	2024-01-11	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 present in population databases (rs63751208, gnomAD 0.007%). This variant has been observed in individuals with HBB-related conditions, usually co-occurring with another severe beta-thalassemia variant (PMID: 2001456, 2713503, 10606872). It has also been observed to segregate with disease in related individuals. Of note, one homozygous individual was reported with beta-thalassemia intermedia (PMID: 30820323). This variant is also known as -101C>T. Studies have shown that this variant alters HBB gene expression (PMID: 2713503). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000820736	SCV001470514	pathogenic	not provided	2020-06-04	criteria provided, single submitter	clinical testing	The c.-151C>T variant (also known as -101(C>T)) is located 101-bp upstream of the transcription initiation site. It causes slightly decreased transcription of the beta-globin gene, and is associated with beta (+)-thalassemia. Approximately one-third of individuals heterozygous for this variant have normal hematologic findings, with the remainder having either a slightly reduced MCH, slightly elevated levels of Hb A2, or a slight globin imbalance (, PMID: 2713503 (1989), 2346726 (1990), 10606872 (1999)).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000820736	SCV001474278	pathogenic	not provided	2023-04-03	criteria provided, single submitter	clinical testing	The HBB c.-151C>T variant (rs63751208, HbVar ID: 649), also known as -101C>T, is associated with silent beta thalassemia in heterozygous carriers and has been described in individuals with a mild form of thalassemia intermedia who were compound heterozygous with a severe beta thalassemia variant (Gonzalez-Redondo 1989, Ristaldi 1990, Rund 1997, see HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 15461). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in a conserved region of the beta globin gene promoter and is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Gonzalez-Redondo JM et al. A C----T substitution at nt--101 in a conserved DNA sequence of the promotor region of the beta-globin gene is associated with "silent" beta-thalassemia. Blood. 1989 May 1;73(6):1705-11. PMID: 2713503 Ristaldi MS et al. The C-T substitution in the distal CACCC box of the beta-globin gene promoter is a common cause of silent beta thalassaemia in the Italian population. Br J Haematol. 1990 Apr;74(4):480-6. PMID: 2346726 Rund D et al. Genetic analysis of beta-thalassemia intermedia in Israel: diversity of mechanisms and unpredictability of phenotype. Am J Hematol. 1997 Jan;54(1):16-22. PMID: 8980256
Revvity Omics, Revvity	RCV000820736	SCV002024961	pathogenic	not provided	2021-06-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000820736	SCV002574669	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant loss of function (Gonzalez-Redondo et al., 1989); Not observed at significant frequency in large population cohorts (gnomAD); Reported as the most common silent beta-thalassemia variant among individuals of Mediterranean background (Maragoudaki et al., 1999); This variant is associated with the following publications: (PMID: 2001456, 7683931, 2346726, 25910213, 2713503, 7909640, 26202972, 28385923, 31395865, 34426522, 10606872)
Fulgent Genetics, Fulgent Genetics	RCV002496384	SCV002809346	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2022-03-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169081	SCV004847530	pathogenic	beta Thalassemia	2022-11-03	criteria provided, single submitter	clinical testing	The c.-151C>T variant in HBB, also known as -101C>T, has been reported in the compound heterozygous state with a severe beta thalassemia variant in numerous individuals with a mild form of thalassemia intermedia. It is the most common silent beta-thalassemia variant among individuals of Mediterranean descent (Gonzalez-Redondo 1989 PMID: 2713503, Ristaldi 1990 PMID: 2346726, Rund 1997 PMID: 8980256, HbVar, Maragoudaki 1999 PMID: 10606872). It has also been reported in ClinVar (Variation ID 15461) and has been identified in 10/68034 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant occurs in the beta-globin promoter, and in vitro functional studies support an impact on promoter activity (Gonzalez-Redondo 1989 PMID: 2713503). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PS4, PM1.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV004566749	SCV005051822	pathogenic	Beta-thalassemia HBB/LCRB	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000016719	SCV000036989	pathogenic	Beta-plus-thalassemia	1999-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000169081	SCV000537286	not provided	beta Thalassemia		no assertion provided	literature only
Natera, Inc.	RCV000169081	SCV002091640	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000169081	SCV004244273	pathogenic	beta Thalassemia	2023-09-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532372	SCV004724943	pathogenic	HBB-related disorder	2023-12-28	no assertion criteria provided	clinical testing	The HBB c.-151C>T variant is located in the 5' untranslated region. This variant, also referred to as c.-101C>T using legacy nomenclature, is predicted to disrupt the CACCC promoter motif and has been reported to be causative for Beta-Thalassemia in the presence of a second pathogenic allele (Gonzalez-Redondo et al. 1989. PubMed ID: 2713503; Rund et al. 1997. PubMed ID: 8980256; Ristaldi et al. 1999. PubMed ID: 10575515). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989290	SCV004806295	uncertain significance	Malaria, susceptibility to	2024-03-25	flagged submission	clinical testing