ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000029 SCV000603872 pathogenic none provided 2020-08-31 criteria provided, single submitter clinical testing The Hb Constant Spring variant (HbCS, HBA2: c.427T>C; p.Ter143GlnextTer31, also known as Ter142Gln when numbered from the mature protein, rs41464951) is usually asymptomatic in the heterozygous state, but may be associated with microcytosis and mild hypochromia. Homozygosity for HbCS is characterized by overt hemolytic anemia, jaundice and splenomegaly, while HbCS paired with an alpha zero-thalassemia deletion commonly results in HbH disease (Lie-Injo 1974, Nguyen 2014, HbVar database). This variant is reported in ClinVar (Variation ID: 15624), and is found in the general population with an overall allele frequency of 0.006% (16/274,340 alleles) in the Genome Aggregation Database. This variant abolishes the canonical termination codon, resulting in an unstable, elongated protein (HbVar database). Based on available information, the HbCS variant is considered to be pathogenic. References: Link to HbVar database for Hb Constant Spring: 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000169546 SCV000746425 pathogenic alpha Thalassemia 2017-12-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508088 SCV000888134 pathogenic not provided 2019-08-23 criteria provided, single submitter clinical testing The variant disrupts the natural stop codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Invitae RCV000508088 SCV000954178 pathogenic not provided 2020-10-15 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.
Myriad Women's Health, Inc. RCV000169546 SCV001194098 pathogenic alpha Thalassemia 2019-12-20 criteria provided, single submitter clinical testing NM_000517.4(HBA2):c.427T>C(*143Qext*31, aka Hb Constant Spring) is classified as pathogenic in the context of alpha thalassemia and is classified as an alpha-plus variant. Sources cited for classification include the following: PMID 4944483, 12393486, 7327587, 2298455 and 17164653. Classification of NM_000517.4(HBA2):c.427T>C(*143Qext*31, aka Hb Constant Spring) is based on the following criteria: This variant is predicted to result in protein elongation in a gene and is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
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
GeneReviews RCV000169546 SCV000503052 pathogenic alpha Thalassemia 2016-12-29 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000169546 SCV001423188 not provided alpha Thalassemia no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 07-24-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.