Submissions for variant NM_001754.5(RUNX1):c.1412_1413dup (p.Leu472fs)

dbSNP: rs1555884790

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004595522	SCV000965642	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-03-26	reviewed by expert panel	curation	The NM_001754.4:c.1412_1413dup (p.Leu472Alafs) variant is a frameshift variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region (removes aa 472-480, including the VWRPY motif) is critical to protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 24353905). This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 24353905). There is evidence of abnormal protein expression of this variant allele as a functional consequence of incorrect protein products (PS3_Moderate; PMID: 24353905). PS3_Moderate is applied because the variant meets PVS1_Strong. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PP1_strong, PS3_moderate, PM2_supporting, PS4_supporting, PM5_supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639524	SCV000761099	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2017-08-12	criteria provided, single submitter	clinical testing	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. This sequence change inserts 2 nucleotides in exon 9 of the RUNX1 mRNA (c.1412_1413dupGC), causing a frameshift at codon 472.  While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acids and to extend the RUNX1 protein beyond the natural translational stop signal by 114 amino acids (p.Leu472Alafs*123). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to segregate with familial platelet disorder with associated myeloid malignancy in a single family (PMID: 24353905, 26492932). Experimental studies have shown that this sequence change creates a stable RUNX1 protein that is visible by Western blot, however the functional consequences of this abnormal protein are unknown (PMID: 24353905). This variant disrupts the VWRPY motif (AAs 476-480) of the RUNX1 protein, which is required for binding to the transcriptional co-repressor Transducin-like enhancer of split (PMID: 9837750, 15749889). Although this motif is required for proper regulation of some RUNX1 target genes (PMID: 15749889, 14504086), deletion of this sequence does not significantly impact hematopoietic development or viability in mice (PMID: 14504086, 10594034). Therefore, the clinical significance of disrupting this domain is uncertain.
PreventionGenetics, part of Exact Sciences	RCV000680391	SCV000807762	likely pathogenic	not provided	2014-01-03	criteria provided, single submitter	clinical testing