ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.1322T>G (p.Leu441Arg)

gnomAD frequency: 0.00001  dbSNP: rs777551786
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV004734140 SCV005367802 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-09-30 reviewed by expert panel curation NM_001754.5(RUNX1):c.1322T>G (p.Leu441Arg) is a missense variant which has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 34166225). 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: PS4_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001350817 SCV001545236 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2024-12-22 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 441 of the RUNX1 protein (p.Leu441Arg). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of RUNX1-related conditions (PMID: 34166225). ClinVar contains an entry for this variant (Variation ID: 1046278). 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. 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.
Baylor Genetics RCV003469586 SCV004209863 uncertain significance Acute myeloid leukemia 2024-02-23 criteria provided, single submitter clinical testing
GeneDx RCV004720865 SCV005327901 uncertain significance not provided 2024-03-13 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; Identified in a patient with B-cell acute lymphoblastic leukemia (ALL) (PMID: 34166225); Functional studies showed the p.(L441R) variant does not significantly decrease in transactivation function in vitro (PMID: 34166225); This variant is associated with the following publications: (PMID: 34166225)

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