Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001374724 | SCV001571653 | pathogenic | Hereditary thrombocytopenia and hematologic cancer predisposition syndrome | 2024-03-26 | reviewed by expert panel | curation | The c.351+1G>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 27931139). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting. |
| Prevention |
RCV000680406 | SCV000807777 | pathogenic | not provided | 2017-03-28 | criteria provided, single submitter | clinical testing | |
| Bone Marrow Failure laboratory, |
RCV001312235 | SCV001502671 | pathogenic | Thrombocytopenia | 2021-01-20 | criteria provided, single submitter | research | This heterozygous, splice variant of RUNX1 was identified in a female with thrombocytopenia, aged 39years (PMID:18723428). Her mother died of CMML (with 11q23 abnormality), maternal uncle died of leukaemia age 64 yrs and maternal cousin had thrombocytopenia and died of AML aged 23 yrs but these individuals were not tested for the variant. The following ACMG/AMP criteria were used: PVS1, PM2 and PP3. |
| Genetic Services Laboratory, |
RCV000680406 | SCV002067373 | pathogenic | not provided | 2019-09-03 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the RUNX1 gene demonstrated a sequence change in the canonical splice donor site of intron 4, c.351+1G>A. This pathogenic sequence change is predicted to affect normal splicing of the RUNX1 gene and result in an abnormal protein which may be degraded, or may lead to the production of a truncated RUNX1 protein with potentially abnormal function. This pathogenic sequence change is absent from population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in multiple patients with RUNX1-related thrombocytopenia (PMIDs:18723428, 28240786, 28102861, 28485484, 27931139). This sequence change is the likely cause of this disease phenotype, however functional studies have not been performed to prove this conclusively. |
| Labcorp Genetics |
RCV002531413 | SCV003443860 | pathogenic | Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 | 2023-08-08 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 4 of the RUNX1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). Disruption of this splice site has been observed in individual(s) with clinical features of RUNX1-related conditions (PMID: 18723428, 27931139, 28102861, 28240786). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 561236). This variant is also known as splice donor site mutation in intron 3. |