ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.380T>A (p.Val127Glu) (rs33925391)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759797 SCV000889369 uncertain significance not provided 2019-03-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000144 SCV001156628 likely pathogenic not specified 2018-12-17 criteria provided, single submitter clinical testing The HBB c.380T>A; Val126Glu variant (rs33925391), also known as Hb Hofu, is reported in the literature in the heterozygous state in both individuals with mild anemia and asymptomatic individuals (Purohit 2014, HbVar database and references therein). This variant was also reported in an individual with thalassemia intermedia who also carried a beta-0 variant (Pande 1995), though it has been described in trans to Hb S in both symptomatic and asymptomatic individuals (Huisman 1997, Purohit 2014, HbVar database). Hematological measurements in carriers indicate that Hb Hofu is a mildly unstable variant (Huisman 1997, Purohit 2014, HbVar database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 126 is moderately conserved, but computational analyses (SIFT: deleterious, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on available information, this variant is considered to be likely pathogenic. References: HbVar entry to Hb Hofu: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=519 Huisman TH et al. Combinations of beta chain abnormal hemoglobins with each other or with beta-thalassemia determinants with known mutations: influence on phenotype. Clin Chem. 1997 Oct;43(10):1850-6. Pande PL et al. Beta-thalassemia intermedia in an Indian female with the Hb Hofu [beta 126(H4)Val-->Glu]-beta zero-thalassemia [codons 8/9 (+G)] combination. Hemoglobin. 1995 Sep;19(5):301-6. Purohit P et al. Clinical and molecular characterization of Hb Hofu in eastern India. Int J Lab Hematol. 2014 Feb;36(1):71-6.
Neuberg Supratech Reference Laboratories Pvt Ltd,Neuberg Centre for Genomic Medicine RCV001507092 SCV001712067 likely pathogenic beta Thalassemia criteria provided, single submitter clinical testing The missense variant NM_000518.5(HBB):c.380T>A (p.Val127Glu) has been previously reported as Hb Hofu and has been observed in Indian population (Pande et al, Purohit et al, Warghade et al). It has been submitted to ClinVar with conflicting interpretations of pathogenicity : VUS/Likely Pathogenic. In combination with a beta 0 variant it has been reported with a thalssemia intermedia phenotype and has been observed in asymptomatic as well as symptomatic indviduals in trans with sickle cell trait (Arends T et al,Brittenham G et al, Purohit et al). The p.Val127Glu variant is novel (not in any individuals) in gnomAD. The p.Val127Glu variant is novel (not in any individuals) in 1kG. There is a moderate physicochemical difference between valine and glutamic acid. In silico tools predict a damaging effect while the residue is weakly conserved across species. For these reasons, this variant has been classified as Likely Pathogenic.
OMIM RCV000016384 SCV000036652 other HEMOGLOBIN HOFU 2017-12-12 no assertion criteria provided literature only

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