ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.27dupG (p.Ser10Valfs*14) (rs35699606)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029974 SCV000052629 pathogenic beta Thalassemia 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000368084 SCV000372530 pathogenic HBB-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The HBB c.27dupG (p.Ser10ValfsTer14) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ser10ValfsTer14 variant, also known as cd8/9+G, is a well-described pathogenic variant. Across a selection of the available literature the p.Ser10ValfsTer14 variant has been reported in at least 229 disease alleles in individuals with HBB-related disorders, including in at least 38 patients in a homozygous state and 30 patients in a compound heterozygous state. The zygosity of the remaining alleles is not known (Kazazian et al. 1984; Villegas et al. 1998; Ansari et al. 2011; Hoppe et al 2013; El-Shanshory et al. 2014; Yasmeen et al. 2016). The variant is reported at frequencies from 1% to 47% depending on the ethnic background but is more common in the South Asian and Middle Eastern populations (Lahiry et al. 2008; Ansari et al. 2011). Control data are unavailable for the p.Ser10ValfsTer14 variant, which is reported at a frequency of 0.00206 in the South Asian population of the Exome Aggregation Consortium. Based on the potential impact of frameshift variants and the supporting evidence from the literature, the p.Ser10ValfsTer14 variant is classified as pathogenic for HBB-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000029974 SCV000538039 pathogenic beta Thalassemia 2016-01-27 criteria provided, single submitter clinical testing The c.27dupG (p.Ser10Valfs*14) frameshift variant in the HBB gene is a well-known variant associated with autosomal recessive Beta-Thalassemia (Baysal, 2005; Sinha et al., 2009; Al-Gazali et al., 2010; Ankala et al., 2015). This variant is predicted to cause a protein termination in exon 1 (out of a total of 3 exons in the coding sequence). Frameshift variants have been described in the HBB gene in several affected individuals and are, therefore, a common mechanism of disease. This variant is located upstream of two heme binding sites and two 2,3-biphosphoglycerate binding sites, and thus, the truncated protein would lack these important binding sites. This c.27dupG has been reported at low frequency in the control population databases (Exome Sequencing Project [ESP] = NA, 1000 Genomes = NA, and ExAC = 0.206%). In silico algorithms predict the resulting transcript will be targeted for the Nonsense Mediated Decay (NMD) Pathway. Therefore, this collective evidence supports the classification of the c.27dupG (p.Ser10Valfs*14) as a recessive Pathogenic variant for Beta-Thalassemia.
GeneDx RCV000479091 SCV000568518 pathogenic not provided 2016-11-11 criteria provided, single submitter clinical testing The c.27dupG variant in the HBB gene has been reported previously using alternate nomenclature c.27_28insG in association with beta-thalassemia when present in the homozygous state or when in trans with another disease-causing variant and is a common pathogenic variant in the Pakistani population (Yasmeen et al., 2016). The c.27dupG variant causes a frameshift starting with codon Serine 10, changes this amino acid to a Valine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Ser10ValfsX14. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.27dupG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.27dupG as a pathogenic variant
Invitae RCV000479091 SCV000939466 pathogenic not provided 2019-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser10Valfs*14) in the HBB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs35699606, ExAC 0.2%). This variant has been observed in numerous individuals and families affected with beta thalassemia and has been reported as a prevalent disease-associated variant in several populations (PMID: 28635337, 9949622, 28391758, 27263053). This variant is also known as CD8/9 (+G), codon 8/9 (+G), FSC 8/9 (+G), and c.27_28insG in the literature. ClinVar contains an entry for this variant (Variation ID: 36308). Loss-of-function variants in HBB are known to be pathogenic (PMID: 7510147, 19269866, 23637309). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001672 SCV001159217 pathogenic not specified 2018-12-12 criteria provided, single submitter clinical testing The HBB c.27dupG; p.Ser10fs variant (also known as Ser9fs when numbered from the mature protein or as Codons 8/9 (+G)) has been reported in individuals with beta-0 thalassemia, both in the homozygous state and in trans to another pathogenic variant (Jalilian 2017, Kazazian 1984, Muhammad 2017, HbVar database and references therein). Consistent with reports that it is prevalent in affected individuals of South Asian descent (Jalilian 2017, Kazazian 1984, Muhammad 2017), this variant is found in the South Asian population with an overall allele frequency of 0.2% (62/30614 alleles) in the Genome Aggregation Database. This variant causes a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to HbVar database for Codons 8/9 (+G): Jalilian M et al. The Frequency of HBB Mutations Among Beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. Kazazian HH Jr et al. Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 1984 Mar;3(3):593-6. Muhammad R et al. Population-Based Genetic Study of Beta-Thalassemia Mutations in Mardan Division, Khyber Pakhtunkhwa Province, Pakistan. Hemoglobin. 2017 Mar;41(2):104-109.
Baylor Genetics RCV001004357 SCV001163293 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000029974 SCV001193932 pathogenic beta Thalassemia 2019-12-19 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.27dupG(S10Vfs*14) 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-zero variant. Sources cited for classification include the following: PMID 22110956, 9949622, 24369358, 6714226, 16821247 and 21509314. Classification of NM_000518.4(HBB):c.27dupG(S10Vfs*14) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Centogene AG - the Rare Disease Company RCV000029974 SCV001424433 pathogenic beta Thalassemia criteria provided, single submitter clinical testing
OMIM RCV000016672 SCV000036942 pathogenic beta^0^ Thalassemia 2017-02-27 no assertion criteria provided literature only
GeneReviews RCV000029974 SCV000040707 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000029974 SCV001244567 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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