Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001287819 | SCV001474550 | pathogenic | Hereditary spherocytosis type 1 | 2023-04-14 | criteria provided, single submitter | clinical testing | The ANK1 c.841C>T; p.Arg281Ter variant is reported in the literature in at least four individuals affected with spherocytosis (Hao 2019, van Vuren 2019). In vitro functional analyses demonstrate increased osmotic fragility and nearly undetected expression of ANK1 (Hao 2019). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Hao L et al. Two novel ANK1 loss-of-function mutations in Chinese families with hereditary spherocytosis. J Cell Mol Med. 2019 Jun. PMID: 31016877 van Vuren A et al. The Complexity of Genotype-Phenotype Correlations in Hereditary Spherocytosis: A Cohort of 95 Patients: Genotype-Phenotype Correlation in Hereditary Spherocytosis. Hemasphere. 2019 Aug. PMID: 31723846 |
| Mayo Clinic Laboratories, |
RCV001508247 | SCV001714282 | pathogenic | not provided | 2024-06-14 | criteria provided, single submitter | clinical testing | PM2_moderate, PM6, PS3, PVS1 |
| Revvity Omics, |
RCV001287819 | SCV003817251 | pathogenic | Hereditary spherocytosis type 1 | 2023-06-12 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001508247 | SCV004535424 | pathogenic | not provided | 2024-12-10 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg281*) in the ANK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANK1 are known to be pathogenic (PMID: 8640229). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features consistent with spherocytosis (PMID: 31016877). ClinVar contains an entry for this variant (Variation ID: 994426). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ANK1 function (PMID: 31016877). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001287819 | SCV005394623 | pathogenic | Hereditary spherocytosis type 1 | 2024-09-25 | criteria provided, single submitter | clinical testing | Variant summary: ANK1 c.841C>T (p.Arg281X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251482 control chromosomes (gnomAD). c.841C>T has been reported in the literature in individuals affected with Hereditary Spherocytosis Type 1 and this variant co-segregated with the disease (Hao_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant disrupts protein function (Hao_2019). The following publication have been ascertained in the context of this evaluation (PMID: 31016877). ClinVar contains an entry for this variant (Variation ID: 994426). Based on the evidence outlined above, the variant was classified as pathogenic. |