ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000029974 SCV000677909 pathogenic beta Thalassemia 2016-02-01 criteria provided, single submitter clinical testing
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
GeneReviews RCV000029974 SCV000040707 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
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.
Integrated Genetics/Laboratory Corporation of America RCV000029974 SCV000052629 pathogenic beta Thalassemia 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000479091 SCV000939466 pathogenic not provided 2018-12-22 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.
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.
OMIM RCV000016672 SCV000036942 pathogenic beta^0^ Thalassemia 2017-02-27 no assertion criteria provided literature only

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