ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.1266G>C (p.Glu422Asp)

gnomAD frequency: 0.00001  dbSNP: rs967317406
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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 RCV004696232 SCV005196474 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-08-16 reviewed by expert panel curation NM_001754.5(RUNX1):c.1266G>C (p.Glu422Asp) is a missense variant which has a REVEL score < 0.50 (0.11) and a SpliceAI score ≤ 0.20 (0.0) (BP4). 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: BP4.
Labcorp Genetics (formerly Invitae), Labcorp RCV000456884 SCV000550166 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2024-12-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 422 of the RUNX1 protein (p.Glu422Asp). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 409823). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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 RCV004568044 SCV005055497 uncertain significance Acute myeloid leukemia 2023-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV004955511 SCV005495316 uncertain significance Inborn genetic diseases 2024-12-07 criteria provided, single submitter clinical testing The p.E422D variant (also known as c.1266G>C), located in coding exon 8 of the RUNX1 gene, results from a G to C substitution at nucleotide position 1266. The glutamic acid at codon 422 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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