Submissions for variant NM_001754.5(RUNX1):c.820C>T (p.Gln274Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV005001451	SCV005627338	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2025-01-15	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.820C>T (p.Q274*) is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/8, leading to nonsense-mediated decay in a gene where loss-of-function is an established disease mechanism (PVS1). This variant is not predicted by SpliceAI to impact splicing and is absent from gnomAD v2, v3, and v4 (PM2_supporting). Although the variant has not been reported in the literature, other null variants in exon 7 have been classified as likely pathogenic (PM5_supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_supporting, PM5_supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003854252	SCV004660027	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-07-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln274*) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. For these reasons, this variant has been classified as Pathogenic.