ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.82G>T (p.Ala28Ser) (rs35424040)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169609 SCV000221131 likely pathogenic beta Thalassemia 2015-02-16 criteria provided, single submitter literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757368 SCV000885562 pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing The Hb Knossos variant (c.82G>T, Ala27Ser) (rs35424040) has been reported in multiple unrelated individuals diagnosed with thalassemia intermedia (Fessas 1982, Orkin 1984, Altay 1990, Sirdah 2013), often found in-trans with other pathogenic HBB variants (Orkin 1984, Altay 1990, Sirdah 2013, HbVar and references therein). The variant is listed in ClinVar (Variation ID: 15239), and observed in the Genome Aggregation Database general population database at a frequency of 0.001 percent (3/246126 alleles). Computational algorithms (GeneSplicer, Human Splicing Finder, MaxEntScan, MutationTaster, NetGene2, NNSplice, SpliceSiteFinder-like) predict that the variant activates a nearby cryptic splice donor upstream of the canonical splice site. Functional studies detected the presence of aberrant mRNA in cells expressing the variant, with a transcript size that is consistent with utilization of the cryptic splice donor predicted by computational algorithms (Orkin 1984). Based on the above information, the Hb Knossos variant is classified as pathogenic. References: Link to HbVar database for Hb Knossos: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=281 Altay C et al. (1990) Beta-thalassemia intermedia in Turkey. Ann N Y Acad Sci. 612:81-9. Fessas P et al. (1982) 'Silent' beta-thalassaemia caused by a 'silent' beta-chain mutant: the pathogenesis of a syndrome of thalassaemia intermedia. Br J Haematol. 51(4):577-83. Orkin S et al. (1984) Abnormal processing of beta Knossos RNA. Blood. 64(1):311-3. Sirdah M et al. (2013) The spectrum of ß-thalassemia mutations in Gaza Strip, Palestine. Blood Cells Mol Dis. 50(4):247-51.
Integrated Genetics/Laboratory Corporation of America RCV000780311 SCV000917478 pathogenic Hemoglobinopathy 2018-05-02 criteria provided, single submitter clinical testing Variant summary: HBB c.82G>T (p.Ala28Ser) results in a conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Although 5/5 computational tools predict no significant impact on normal splicing, all 5 tools predict the presence of a cryptic 5' donor site upstream of the canonical splice site. These predictions are supported by a study that showed the presence of an alternative transcript for c.82G>T (Orkin_1984). The variant allele was found at a frequency of 1.2e-05 in 247346 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in HBB causing Beta Thalassemia (1.2e-05 vs 1.10e-02), allowing no conclusion about variant significance. The variant, c.82G>T, has been reported in the literature in multiple individuals affected with Beta Thalassemia (Orkin_1984, Baklouti_1986, El-Kalla_1997, Tadmouri_1998, Sirdah_2013, Nasouhipur_2014). Clinical presentation ranged from mild to severe b-thal intermedia with a varying need for transfusions depending on the second pathogenic allele found. Based on the published reports, most cases have been diagnosed relatively late in childhood or puberty and some are much later in adulthood. Oxygen affinity studies showed a significantly decreased affinity for p.A28S for both heterozygous carriers and Hb Knossos-b-thalassemia compound heterozygotes (Fessas_1986). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000757368 SCV000942026 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 28 of the HBB protein (p.Ala28Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs35424040, ExAC 0.001%). This variant has been observed in individual(s) with beta-thalassemia major or intermedia (PMID: 6469698, 9223924, 17949282, 2467892). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Hb Knossos, Cd27, and Ala27Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 15239). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 6733281). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016439 SCV000036707 other HEMOGLOBIN KNOSSOS 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016440 SCV000036708 pathogenic Beta-plus-thalassemia 1989-01-01 no assertion criteria provided literature only
OMIM RCV000016441 SCV000036709 pathogenic Beta-knossos-thalassemia 1989-01-01 no assertion criteria provided literature only
GeneReviews RCV000169609 SCV000537296 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only

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