ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.351+2T>A

dbSNP: rs2057997150
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV002264769 SCV002546442 likely pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2022-04-24 reviewed by expert panel curation The c.351+2T>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and is expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1 and PM2_supporting
Labcorp Genetics (formerly Invitae), Labcorp RCV001213758 SCV001385407 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2022-10-28 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 943551). Disruption of this splice site has been observed in individual(s) with clinical features of RUNX1-related conditions (PMID: 27931139, 28240786). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the RUNX1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448).

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