Submissions for variant NM_001754.5(RUNX1):c.1336C>T (p.Leu446Phe)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV005001412	SCV005627357	uncertain significance	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2025-01-15	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.1336C>T (p.Leu446Phe) is a missense variant predicted to substitute leucine with phenylalanine at amino acid 446. This variant is absent from gnomAD v2, v3, and v4 (PM2_supporting) and has not been reported in relevant cases in the literature. The computational predictor REVEL gives a score of 0.315, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicates no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting and BP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003629510	SCV004387708	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 446 of the RUNX1 protein (p.Leu446Phe). 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. 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. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency).