ClinVar Miner

Submissions for variant NM_001754.4(RUNX1):c.958C>T (p.Arg320Ter) (rs1569008655)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV001078218 SCV001244327 pathogenic Familial platelet disorder with associated myeloid malignancy 2020-01-14 reviewed by expert panel curation The NM_001754.4:c.958C>T (p.Arg320Ter) variant is a nonsense variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region (removes aa 320 - 480) is critical to protein function (PVS1_Strong). This variant was found to co-segregate with disease in multiple affected family members, with more than seven (14) meioses observed across 2 families (PP1_Strong; from internal laboratory data). The variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; from internal laboratory data). 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_Strong, PP1_Strong, PM2, PS4_Moderate.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757724 SCV000886060 pathogenic not provided 2018-01-25 criteria provided, single submitter clinical testing The RUNX1 c.958C>T; p.Arg320Ter variant, also known as R292X, is reported in the germline of individuals with familial platelet disorder with associated myeloid malignancies (FPDMM) (Owen 2008, Patton 2007, Rossini 2012). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon; since it occurs toward the end of the penultimate exon the transcript is less likely to be subject to nonsense-mediated decay and more likely to yield a truncated protein, but mRNA nonsense-mediated decay cannot be ruled out. Based on available information, this variant is considered pathogenic. REFERENCES Owen CJ et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood. 2008 Dec 1;112(12):4639-45. Patton WN et al. Novel Heritable Mutation of the Transcription Factor RUNX1 as a Cause of Autosomal Dominant Familial Platelet Disorder with Predisposition to Acute Myeloid Leukemia (FPD/AML). Blood 2007 110:4244. Rossini et al. Familial platelet disorders with a predisposition to acute myelogenous leukaemia: a RUNX1 update. Hereditary Cancer in Clinical Practice 2012. 10(Suppl 2)A64.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851916 SCV000899997 likely pathogenic Thrombocytopenia 2019-02-01 criteria provided, single submitter research
Invitae RCV001078218 SCV001575462 likely pathogenic Familial platelet disorder with associated myeloid malignancy 2020-06-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the RUNX1 gene (p.Arg320*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 161 amino acids of the RUNX1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of familial platelet disorder with associated myeloid malignancies (PMID: 18723428, 31064749, 25840971, external communications). It has also been observed to segregate with disease in related individuals. This variant is also known in the literature as c.877C>T (R292*). ClinVar contains an entry for this variant (Variation ID: 618862). This variant has been reported to affect RUNX1 protein function (PMID: 25840971). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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.