ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.508+3del

dbSNP: rs587776810
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV004700241 SCV000965629 pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-09-10 reviewed by expert panel curation There is RT-PCR assay evidence demonstrating that the NM_001754.4:c.508+3delA variant creates a cryptic splice donor site that is used and results in a frameshift and introduction of premature termination codon (PS3; PMID: 11830488). This variant was found to co-segregate with disease in multiple affected family members, with eight meioses observed in one family (PP1_Strong; PMID: 11830488). It is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This intronic variant (in intron 5) is located in reference to the exon at positions +3 for donor splice site and has a predicted decrease in the score of the canonical splice site by at least 75% (measured by both MES and SSF). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 11830488). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PP1_Strong, PM2_supporting, PP3, PS4_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000015552 SCV000638145 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2018-03-10 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the RUNX1 gene. It does not directly change the encoded amino acid sequence of the RUNX1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a single family and reported to segregate with disease in several family members affected with a bleeding disorder and platelet defect (where studied). Four of the family members also had leukemia (PMID: 11830488). ClinVar contains an entry for this variant (Variation ID: 14466). Experimental RT-PCR studies, using RNA derived from two of the affected family members, have shown that this intronic variant disrupts splicing through the use of a novel cryptic splice site 23 nucleotides upstream of the normal splice site. This is expected to lead to a frameshift and premature termination codon (p.Arg135fs*177). Experimental analysis of this truncated RUNX1 protein showed that it had lost its DNA-binding, heterodimerization, nuclear localization, and transactivation functions (PMID: 11830488). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015552 SCV000035817 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2002-02-15 no assertion criteria provided literature only

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