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

gnomAD frequency: 0.00002  dbSNP: rs35424040

Total submissions: 14

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	2023-06-26	criteria provided, single submitter	clinical testing	The Hb Knossos variant (HBB: c.82G>T; p.Ala28Ser, also known as Ala27Ser when numbered from the mature protein, rs35424040, HbVar ID: 281) has been reported in multiple unrelated individuals diagnosed with thalassemia intermedia (Altay 1990, Fessas 1982, Orkin 1984, Sirdah 2013), often found in-trans with other pathogenic HBB variants (Altay 1990, Orkin 1984, Sirdah 2013, HbVar and references therein). This variant is listed in ClinVar (Variation ID: 15239), and found in the general population with an overall allele frequency of 0.001% (3/251362 alleles) in the Genome Aggregation Database. Computational analyses predict that the variant activates a nearby cryptic splice donor upstream of the canonical splice site (Alamut v.2.11). 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 available information, the Hb Knossos variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Altay C et al. Beta-thalassemia intermedia in Turkey. Ann N Y Acad Sci. 1990; 612:81-9. PMID: 2291577 Fessas P et al. 'Silent' beta-thalassaemia caused by a 'silent' beta-chain mutant: the pathogenesis of a syndrome of thalassaemia intermedia. Br J Haematol. 1982; 51(4):577-83. PMID: 7104238 Orkin S et al. Abnormal processing of beta Knossos RNA. Blood. 1984; 64(1):311-3. PMID: 6733281 Sirdah M et al. The spectrum of B-thalassemia mutations in Gaza Strip, Palestine. Blood Cells Mol Dis. 2013; 50(4):247-51. PMID: 23321370
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 28 of the HBB protein (p.Ala28Ser). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs35424040, gnomAD 0.007%). This missense change has been observed in individual(s) with beta-thalassemia major or intermedia (PMID: 2467892, 6469698, 9223924, 17949282). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Hb Knossos, Cd27, and Ala27Ser. 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 6733281). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004353	SCV001163288	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169609	SCV001810472	pathogenic	beta Thalassemia	2021-07-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000757368	SCV002774342	pathogenic	not provided	2021-06-23	criteria provided, single submitter	clinical testing	The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant has been shown to be damaging to protein function(s) relevant to disease mechanism.
GeneDx	RCV000757368	SCV003919670	pathogenic	not provided	2023-03-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as RNA transcripts are abnormally processed (Orkin et al., 1984); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25155404, 19429541, 25087612, 25332589, 3955238, 17949282, 26754299, 31553106, 3942130, 6469698, 28399358, 2467892, 9223924, 30777047, 6733281)
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	not provided	beta Thalassemia		no assertion provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000169609	SCV001244425	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000780311	SCV001453788	pathogenic	Hemoglobinopathy	2020-09-16	no assertion criteria provided	clinical testing