ClinVar Miner

Submissions for variant NM_000517.4(HBA2):c.427T>C (p.Ter143Gln) (rs41464951)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508088 SCV000603872 pathogenic not provided 2017-06-12 criteria provided, single submitter clinical testing The Hb Constant Spring variant (c.427T>C; Ter142Gln) (rs41464951) has been reported heterozygously in multiple individuals with microcytosis and mild hypochromia, and can cause alpha thalassemia when found homozygously or with other pathogenic alpha globin variants (Lie-Injo 1974, Nguyen 2014, HbVar database and references therein). It is reported as pathogenic in ClinVar (Variation ID: 15624) and observed in the general population at an overall frequency of 0.006% (16/274340 alleles) in the Genome Aggregation Database. This variant abolishes the canonical termination codon, resulting in an elongated protein that is unstable (HbVar database and references therein). Based on available information, this variant is considered pathogenic. REFERENCES Link to HbVar database for Hb Constant Spring: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=703 Lie-Injo L et al. Homozygous state for Hb Constant Spring (slow-moving Hb X components). Blood. 1974 Feb;43(2):251-9. Nguyen V et al. Hemoglobin Constant Spring is markedly high in women of an ethnic minority group in Vietnam: a community-based survey and hematologic features. Blood Cells Mol Dis. 2014 Apr;52(4):161-5.
Counsyl RCV000169546 SCV000221037 pathogenic alpha Thalassemia 2015-01-15 criteria provided, single submitter literature only
GeneReviews RCV000169546 SCV000503052 pathogenic alpha Thalassemia 2016-12-29 no assertion criteria provided literature only
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000169546 SCV000746425 pathogenic alpha Thalassemia 2017-12-03 criteria provided, single submitter clinical testing
Invitae RCV000508088 SCV000954178 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing This sequence change disrupts the translational stop signal of the HBA2 mRNA. It is expected to extend the length of the HBA2 protein by 31 additional amino acid residues. This variant is present in population databases (rs41464951, ExAC 0.05%). This is the most common variant associated with non-deletional alpha-thalassemia or hemoglobin H disease, and is considered a founder variant in the Southeast Asian population (PMID: 4944483, 2298455, 12393486, 20507641). It is commonly known as the "Constant Spring" variant. ClinVar contains an entry for this variant (Variation ID: 15624). Experimental studies have shown that red blood cells derived from individuals homozygous for this variant exhibit a number of cell and membrane abnormalities (PMID: 6725554, 9057661). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016891 SCV000037161 other Hemoglobin constant spring 2018-05-21 no assertion criteria provided literature only
OMIM RCV000022602 SCV000043891 pathogenic Hemoglobin H disease, nondeletional 1992-01-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508088 SCV000888134 pathogenic not provided 2015-07-29 criteria provided, single submitter clinical testing

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