Submissions for variant NM_001754.5(RUNX1):c.958C>T (p.Arg320Ter)

dbSNP: rs1569008655

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004595532	SCV001244327	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-03-26	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_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). 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_supporting, PS4_Moderate, PM5_supporting.
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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001078218	SCV001575462	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-08-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the RUNX1 protein. Other variant(s) that disrupt this region (p.Ser322*) have been observed in individuals with RUNX1-related conditions (PMID: 31989091). This suggests that this may be a clinically significant region of the protein. Experimental studies have shown that this premature translational stop signal affects RUNX1 function (PMID: 22318203, 25840971). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 618862). This variant is also known as c.877C>T (R292X). This premature translational stop signal has been observed in individual(s) with clinical features of familial platelet disorder and associated myeloid malignancies (PMID: 18723428, 25840971, 31064749, 32208489; external communications). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg320*) in the RUNX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 161 amino acid(s) of the RUNX1 protein.