Submissions for variant NM_001754.5(RUNX1):c.146C>T (p.Pro49Leu)

gnomAD frequency: 0.00001  dbSNP: rs752298116

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV003405282	SCV004123182	uncertain significance	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2023-11-13	reviewed by expert panel	curation	In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: No codes met.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064297	SCV001229189	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2024-03-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 49 of the RUNX1 protein (p.Pro49Leu). This variant is present in population databases (rs752298116, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 858424). Advanced 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 at Invitae 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. 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.
Genetic Services Laboratory, University of Chicago	RCV001819791	SCV002067883	uncertain significance	not specified	2021-09-21	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RUNX1 gene demonstrated a sequence change, c.146C>T, in exon 4 that results in an amino acid change, p.Pro49Leu. This sequence change has been described in the gnomAD database with a frequency of 0.0058% in the Latino/Admixed American subpopulation (dbSNP rs752298116). The p.Pro49Leu change affects a moderately conserved amino acid residue located in a domain of the RUNX1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro49Leu substitution. This sequence change does not appear to have been previously described in individuals with RUNX1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro49Leu change remains unknown at this time.
GeneDx	RCV002462310	SCV002756815	uncertain significance	not provided	2022-05-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003467823	SCV004209874	uncertain significance	Acute myeloid leukemia	2023-05-11	criteria provided, single submitter	clinical testing