rs74315450
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP1PP3PS4PS3
This summary comes from the ClinGen Evidence Repository: Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.602G>A (p.Arg201Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID:17290219, 11830488, 23817177, 22318203, 25840971, 23848403). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMID:27112265, 28748566, 10508512). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). The variant has a REVEL score >0.75 (0.94) (PP3). It was found to co-segregate with disease in multiple affected family members, with four meioses observed in across 3 families (PP1; PMID:27112265, 28748566, 10508512). 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, PS4, PM1, PM2, PP1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA248610/MONDO:0011071/008
Frequency
Consequence
NM_001754.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RUNX1 | NM_001754.5 | c.602G>A | p.Arg201Gln | missense_variant | 6/9 | ENST00000675419.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RUNX1 | ENST00000675419.1 | c.602G>A | p.Arg201Gln | missense_variant | 6/9 | NM_001754.5 | A1 | ||
RUNX1-AS1 | ENST00000651798.1 | n.661+22539C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460892Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726878
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene, and are associated with acute myeloid leukaemia (MIM#601626) and familial platelet disorder with associated myeloid malignancy (MIM#601399) (PMID: 28179279). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated runt domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been classified as pathogenic by the ClinGen Myeloid Malignancy Variant Curation Expert Panel (ClinVar). It has been reported in multiple individuals with myelodysplastic syndrome or thrombocytopenia (PMIDs: 27112265, 28748566). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, reviewed by expert panel | curation | ClinGen Myeloid Malignancy Variant Curation Expert Panel | Jul 30, 2019 | Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.602G>A (p.Arg201Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBF-beta binding and sub-cellular localization (PS3; PMID: 17290219, 11830488, 23817177, 22318203, 25840971, 23848403). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMID: 27112265, 28748566, 10508512). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). The variant has a REVEL score >0.75 (0.94) (PP3). It was found to co-segregate with disease in multiple affected family members, with four meioses observed in across 3 families (PP1; PMID: 27112265, 28748566, 10508512). 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, PS4, PM1, PM2, PP1, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 201 of the RUNX1 protein (p.Arg201Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of platelet dysfunction, mild to moderate thrombocytopenia, and myeloid malignancies (PMID: 10508512, 21725049, 27112265). It has also been observed to segregate with disease in related individuals. This variant is also known as R174Q. ClinVar contains an entry for this variant (Variation ID: 14464). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RUNX1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 11830488, 21725049, 22898599, 25490895). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at