ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.341T>A (p.Val114Glu)

gnomAD frequency: 0.00001  dbSNP: rs34484056
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000016516 SCV001361818 uncertain significance not specified 2021-05-27 criteria provided, single submitter clinical testing Variant summary: HBB c.341T>A (p.Val114Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 630098 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.00051 vs 0.011), allowing no conclusion about variant significance. Compound heterozygotes of c.341T>A and a beta thalassmia mutation have been reported in the literature in individuals affected with sickling disorder symptoms (McFarlane_2011). However, similar compound heterozygotes have been reported in patients without significant clinical symptoms (Zeng_1982, Lee_2008). In addition, compound heterozygotes of c.341T>A and an alpha-thalassemia allele have also been reported in patients without significant clinical symptoms (Ranney_1967, Chaibunruang_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284155 SCV001469781 uncertain significance not provided 2023-06-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001284155 SCV001471915 likely pathogenic not provided 2023-10-17 criteria provided, single submitter clinical testing The Hb New York variant (HBB: c.341T>A; p.Val114Glu, also known as Val113Glu when numbered from the mature protein, HbVar ID: 491) is reported in the heterozygous state in individuals with no associated hematological symptoms, and did not affect clinical symptoms when occurring in-trans with beta thalassemia or hemoglobin E, or when coinherited with alpha thalassemia trait (Chaibunruang 2018, Ranney 1967, Todd 1980, HbVar database and references therein). However, this variant is reported to contribute to a clinically significant sickling disorder in individuals who also carry the hemoglobin S allele (Calder 2012, McFarlane 2011). This variant is reported in ClinVar (Variation ID: 15286), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 114 is highly conserved, and results in a mildly unstable variant protein and reduced oxygen affinity (HbVar database and references therein). Based on available information, the Hb New York variant is considered likely pathogenic for sickling disease when found with HbS, although there is no evidence that it is disease-associated alone or in trans with a beta-thalassemia variant. References: Link to HbVar for HB New York: https://globin.bx.psu.edu/hbvar/menu.html Calder D et al. Sickle retinopathy in a person with hemoglobin s/new york disease. Case Rep Genet. 2012;2012:136582. PMID: 23346429. Chaibunruang A et al. Molecular Characteristics of Hb New York (B113(G15)Val?Glu, HBB: c.341T>A) in Thailand. Hemoglobin. 2018 Jan;42(1):11-15. PMID: 29464999. McFarlane A et al. A novel sickling hemoglobinopathy. N Engl J Med. 2011 Oct 20;365(16):1548-9. PMID: 22010933. Ranney HM et al. Haemoglobin New York. Nature. 1967 Mar 4;213(5079):876-8. PMID: 6030043. Todd D et al. Globin chain synthesis in haemoglobin New York (beta 113 replaced by glutamic acid). Br J Haematol. 1980 Dec;46(4):557-64. PMID: 7437334.
GeneDx RCV001284155 SCV003929598 uncertain significance not provided 2022-11-21 criteria provided, single submitter clinical testing Reported in unrelated patients with features of sickle cell trait; however, these patients also harbored the c.20A>T common variant (McFarlane et al., 2011; Calder et al., 2012); Also observed in patients referred for carrier screening and have normal hemoglobin testing (Lin et al., 2013; van Zwieten et al., 2014; Lou et al., 2014; Huang et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Hb New York or Hb Kaohsiung; This variant is associated with the following publications: (PMID: 24200101, 24099628, 1428942, 12403232, 28865746, 24055728, 19631632, 18432506, 1634358, 25089872, 31980563, 29626415, 36053226, 22010933, 19429541, 30837609, 29464999, 28143837, 24985555, 23346429, 23383304)
OMIM RCV000016516 SCV000036784 pathogenic not specified 1980-12-01 no assertion criteria provided literature only

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