Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001000071 | SCV000883973 | pathogenic | not specified | 2018-11-06 | criteria provided, single submitter | clinical testing | The Hb Rotterdam variant (HBA2: c.98T>G; p.Met33Arg, also known as Met32Arg when numbered from the mature protein; rs1468615416) is reported to be a hyperunstable variant that is associated with mild microcytic hypochromic anemia in individuals who carry the variant homozygously or with the -3.7kb deletion (Giordano 2010, see HbVar link). Additionally, a different alteration at this codon (Hb Amsterdam, p.Met33Ile) is also reported to be a hyperunstable variant associated with microcytic hypochromic anemia (Harteveld 2005). The Hb Rotterdam variant is found in the general population with a low allele frequency of 0.001% (1/94004 alleles) in the Genome Aggregation Database. The methionine at residue 33 is weakly conserved, but computational algorithms (SIFT, PolyPhen2, MutationTaster) predict the p.Met33Arg variant to be deleterious, though these predictions are low confidence. Although the nucleotide variant occurs near the intron-exon junction, in silico tools do not predict any significant effect on mRNA splicing. The instability of the Hb Rotterdam variant was proposed to result from molecular instability associated with the importance of Met33 in alpha-beta contact, but no experiments were reported that would demonstrate whether a stable mRNA is transcribed (Giordano 2010). Based on the above information, Hb Rotterdam is considered likely pathogenic. References: Link to HbVar database for Hb Rotterdam: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2980&.cgifields=histD Giordano PC et al. Codon 24 (TAT>TAG) and codon 32 (ATG>AGG) (Hb Rotterdam): two novel alpha2 gene mutations associated with mild alpha-thalassemia found in the same family after newborn screening. Hemoglobin. 2010;34(4):354-65. Harteveld CL et al. Hb Amsterdam [alpha32(B13)Met--Ile (alpha2)]: a new unstable variant associated with an alpha-thalassemia phenotype and a new African polymorphism. Hemoglobin. 2005;29(4):257-62. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000756228 | SCV001134206 | uncertain significance | not provided | 2024-07-02 | criteria provided, single submitter | clinical testing | The HBA2 c.98T>G (p.Met33Arg) variant has been reported in the published literature in homozygous, heterozygous and in association with alpha-thal 3.7 deletion or HbS in mild anemic individuals with mild to moderate microcytosis and hypochromia (PMID: 20642333 (2010), 26485748 (2016), HbVar ( http://globin.cse.psu.edu/cgi-bin/hbvar/counter)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323709 | SCV004028770 | likely pathogenic | alpha Thalassemia | 2023-07-20 | criteria provided, single submitter | clinical testing | Variant summary: HBA2 c.98T>G (p.Met33Arg), also known as Hb Rotterdam (Giordano_2010) and Hb Gran Via (delaFuente-Gonzalo_2016), 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. In addition, this variant disrupts the third nucleotide of exon 2, and therefore can affect splicing. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1e-05 in 98938 control chromosomes (i.e., 1 heterozygote; gnomAD v2.1 Exomes dataset). c.98T>G has been reported in the literature in mulitple individuals affected with microcytic hypochromic anemia (e.g., Giordano_2010, DelaFuente-Gonzalo_2016, Fjeld_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20642333, 26485748, 36567661). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |