ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.262A>C (p.Thr88Pro) (rs35553496)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000508492 SCV000052628 likely benign not specified 2019-11-22 criteria provided, single submitter clinical testing Variant summary: HBB c.262A>C (p.Thr88Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 252054 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant is found in 1.8% of the Maltese population (Kutlar_1991) and happens to be in tight linkage disequilibrium with the fetal Hb variant Hb F-Malta-I (HBG2 c.353A>G (p.His118Arg)). The variant has been reported in individuals in compound heterozygosity with a beta-thal causing variant (c.93+6T>C) whose hematological findings were similar to those detected in a simple heterozygous state (thalassemia trait), providing supportive evidence for a benign role (Scerri_1993). At least one publication, Kutlar_1991, reported heat stability experiments on mixtures of equal quantities of Hb A and Hb Valletta and on red cell lysates of two adult Hb Valletta heterozygotes, and showed normal stability. Another ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508492 SCV000603921 likely benign not specified 2018-08-27 criteria provided, single submitter clinical testing The HBB c.262A>C; Thr87Pro variant, also known as Hb Valletta, is reported in the literature, typically in linkage to the Hb F-Malta-I variant, in individuals affected with beta-thalassemia (Perrinello 2008, Scerri 1993) and in healthy individuals (Giambona 2006, Kutlar 1991, HbVar database and references therein). One individual with beta-thalassemia who carried the Thr87Pro variant was also homozygous for a pathogenic HBB variant (Parrinello 2008). Heat stability assays on Thr87Pro variant protein indicate this variant has normal stability (Kutlar 1991). The variant is listed ClinVar (Variation ID: 15489) and is found in the non-Finnish European population on six chromosomes in the Genome Aggregation Database. The threonine at residue 87 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on available information, the variant is considered likely benign. References: Link to HbVar database for Hb Valletta: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=417 Giambona A et al. Analysis of delta-globin gene alleles in the Sicilian population: identification of five new mutations. Haematologica. 2006 Dec;91(12):1681-4. Kutlar F et al. The linkage of Hb Valletta [alpha 2 beta 287(f3)Thr----Pro] and Hb F-Malta-I [alpha 2G gamma 2117(G19)His----Arg] in the Maltese population. Hum Genet. 1991 Apr;86(6):591-4. Perrinello G et al. Fever of unclear origin and cytopenia because of acute splenic sequestration in a young immunocompetent carrier of beta-globin mutation for Hb Valletta. Am J Med Sci. 2008 Dec;336(6):508-11. Scerri CA et al. The beta + IVS, I-NT no. 6 (T --> C) thalassaemia in heterozygotes with an associated Hb Valletta or Hb S heterozygosity in homozygotes from Malta. Br J Haematol. 1993 Apr;83(4):669-71.
Mendelics RCV000029973 SCV001138216 benign beta Thalassemia 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000016749 SCV000037019 other HEMOGLOBIN VALLETTA 2017-12-12 no assertion criteria provided literature only

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