Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001284145 | SCV001469771 | uncertain significance | not provided | 2020-01-30 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV001284145 | SCV002058036 | benign | not provided | 2021-04-28 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001824910 | SCV002074517 | benign | not specified | 2022-01-04 | criteria provided, single submitter | clinical testing | Variant summary: HBA2 c.301-24delinsCTCGGCCC is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was not found in the gnomAD database, however two smaller insertion variants, described as 16-223445-C-CCCT and 16-223447-G-GGCCC are reported, which together (i.e.in cis) would result in an equivalent change to our variant of interest, and in all individuals with read data available these variants were reported in cis. This composite variant is found at a frequency of 1.8e-05 in 277312 control chromosomes in the gnomAD database, including 2 homozygotes (exclusively reported in the African subpopulation). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.301-24delinsCTCGGCCC, has been reported in the literature in individuals affected with (suspected) Alpha Thalassemia or other hematological phenotypes (e.g. Phylipsen_2010, Origa_2014, Pedroso_2017), however in at least one of these cases a co-occurring potentially pathogenic variant was also reported, which could explain the phenotype (Pedroso_2017). In addition, one study showed no significant difference in hematological parameters between newborns positive or negative for the presence of this variant, confirming that it has no a-thalassemia effect (Segbena_1998). In this study the variant was also described to be found in cis with the polymorphism c.300+55T>G (aka. c.301-88T>G), and authors referred to the complex as the known "African alpha2 polymorphism marker". Another study also reported these variants in cis, and referred to the complex as the "alpha212 patchwork allele" due to its alternating alpha2, alpha1, and alpha2 sequences, since two sites within the intron 2 of the HBA2 gene have been replaced by HBA1-specific sequences; and found it in individuals of different ethnicity, geographical origin, and haplotype backgrounds, thus suggesting that this alpha-globin patchwork allele has arisen independently on several occasion (Law_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=1), or benign (n=2). Based on the evidence outlined above, the variant was classified as benign. |
| The ITHANET community portal, |
RCV001078245 | SCV001244387 | benign | alpha Thalassemia | 2019-11-25 | no assertion criteria provided | curation |