Submissions for variant NM_001754.5(RUNX1):c.601C>T (p.Arg201Ter)

dbSNP: rs1057519748

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004701462	SCV000965612	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-09-04	reviewed by expert panel	curation	The NM_001754.4:c.601C>T (p.Arg201Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMIDs: 10508512; 19387465; 20549580; 28513614). The variant was found to co-segregate with disease in multiple affected family members, with 14 meioses observed in across 4 families (PP1_Strong; PMID: 10508512; 19387465; 20549580; 28513614). The variant is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). 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, PS4, PP1_Strong, PM2_supporting.
GeneDx	RCV001753852	SCV002007239	pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also published as Arg174Ter; This variant is associated with the following publications: (PMID: 32477529, 26884589, 19387465, 28513614, 10508512, 20549580, 25525159, 25159113, 28102861, 31124578, 23848403, 30600763, 32554555)
Genetic Services Laboratory, University of Chicago	RCV001753852	SCV002067300	pathogenic	not provided	2019-04-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RUNX1 gene demonstrated a sequence change, c.601C>T, which results in the creation of a premature stop codon at amino acid position 201, p.Arg201*. This pathogenic sequence change is predicted to result in an abnormal transcript, 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 (Ripperger et al., 2009; Yoshima et al., 2016; Tawana et al., 2017).
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000824700	SCV002500913	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824700	SCV003443836	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2022-08-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 376018). This premature translational stop signal has been observed in individual(s) with acute myelogenous leukemia and/or familial thrombocytopenia (PMID: 10508512). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg201*) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000824700	SCV004807352	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2024-03-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004022198	SCV005018254	pathogenic	Inborn genetic diseases	2023-12-20	criteria provided, single submitter	clinical testing	The p.R201* pathogenic mutation (also known as c.601C>T), located in coding exon 5 of the RUNX1 gene, results from a C to T substitution at nucleotide position 601. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been reported in multiple individuals in the literature with a personal and/or family history of thrombocytopenia and/or hematologic malignancies (examples: Tawana K et al. Eur J Hum Genet. 2017 Aug;25(8):1020-1024; Ansar S et al. Genet Med. 2022 Nov;24(11):2367-2379; Liu C et al. EJHaem . 2023 Feb;4(1):145-152). In addition, this variant was reported to segregate with disease in multiple affected family members (Tawana K et al. Eur J Hum Genet. 2017 Aug;25(8):1020-1024; Liu C et al. EJHaem. 2023 Feb;4(1):145-152). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Database of Curated Mutations (DoCM)	RCV000422235	SCV000504771	likely pathogenic	Acute myeloid leukemia	2014-10-02	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003932542	SCV004749994	pathogenic	RUNX1-related disorder	2024-02-16	no assertion criteria provided	clinical testing	The RUNX1 c.601C>T variant is predicted to result in premature protein termination (p.Arg201*). This variant has been reported in several families with familial platelet disorder and hematologic malignancies (see for example Sood et al. 2017. PubMed ID: 28179279). Other RUNX1 gene variants that cause premature protein termination of the RUNX1 protein have been reported in numerous patients with thrombocytopenia and myeloid malignancies (Song et al. 1999. PubMed ID: 10508512; Buijs et al. 2012. PubMed ID: 22430633; Shiba et al. 2012. PubMed ID: 22138511). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in RUNX1 are expected to be pathogenic. In summary, the RUNX1 gene variant p.Arg201* is the type of variant expected to be a primary cause of disease and may also be associated with myeloid malignancy predisposition.