Submissions for variant NM_001754.5(RUNX1):c.259G>T (p.Gly87Cys)

gnomAD frequency: 0.00003  dbSNP: rs561166961

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV000527760	SCV000965650	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2019-07-26	reviewed by expert panel	curation	The NM_001754.4:c.259G>T (p.Gly87Cys) variant is a missense variant has a REVEL score >0.75 (0.918) (PP3). AMR Subpopulation of 1000 Genomes Allele frequency 0.00144 with 1 allele out of 694 alleles. In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3.
Genetic Services Laboratory, University of Chicago	RCV000503460	SCV000596882	uncertain significance	not specified	2017-03-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527760	SCV000638138	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 87 of the RUNX1 protein (p.Gly87Cys). This variant is present in population databases (rs561166961, gnomAD 0.003%). This missense change has been observed in individual(s) with iMCD-TAFRO syndrome (PMID: 31309983, 32051554). This variant is also known as p.Gly60Cys. ClinVar contains an entry for this variant (Variation ID: 436618). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RUNX1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RUNX1 function (PMID: 32051554, 33692461). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000527760	SCV004807431	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2024-03-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004568638	SCV005055508	uncertain significance	Acute myeloid leukemia	2023-11-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000680398	SCV005327672	uncertain significance	not provided	2024-02-28	criteria provided, single submitter	clinical testing	Observed in the germline of individuals with pediatric B-ALL and iMCD-TAFRO (PMID: 31309983, 34166225); Published functional studies are conflicting regarding the effect of this variant on transcriptional activity and protein production (PMID: 32051554, 34166225, 33692461); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(G60C); This variant is associated with the following publications: (PMID: 34859285, 23819521, 31978184, 33692461, 32051554, 34166225, 31309983)
PreventionGenetics, part of Exact Sciences	RCV004742464	SCV000807769	uncertain significance	RUNX1-related disorder	2024-06-27	no assertion criteria provided	clinical testing	The RUNX1 c.259G>T variant is predicted to result in the amino acid substitution p.Gly87Cys. This variant has been reported in the literature in several individuals with iMCD-TAFRO syndrome and in a pediatric B-ALL patient (Weinberg et al. 2019, Table 4. PubMed ID: 31309983; Yoshimi et al. 2020, Table 2. PubMed ID: 32051554; Li et al. 2021, Table 1. PubMed ID: 34166225; Decker et al. 2021, Table B. PubMed ID: 33692461). Functional studies are inconclusive regarding the pathogenicity of this variant (Yoshimi et al. 2020. PubMed ID: 32051554; Decker et al. 2021. PubMed ID: 33692461; Li et al. 2021. PubMed ID: 34166225). This variant is alternatively referred to as c.178G>T p.Gly60Cys (NM_001001890) in the literature. This variant is absent in a large population database, indicating this variant is rare. This variant is interpreted as a variant of uncertain significance by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/436618/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center	RCV000824697	SCV000965596	likely pathogenic	Castleman-Kojima disease	2019-08-12	no assertion criteria provided	clinical testing