Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001290699 | SCV001478836 | likely pathogenic | Hereditary thrombocytopenia and hematologic cancer predisposition syndrome | 2021-01-12 | reviewed by expert panel | curation | This missense variant has not been reported in gnomAD (v2 and v3) [PM2]. It has been reported as a germline variant in an unaffected proband (30s) who had a suggestive family history, including thrombocytopenia and AML (SCV001375396.1); however, all other reports of the variant are not clearly germline (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 30373888, 31649132, 32045476, 32208489). The variant is located at a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is considered a hotspot residue (PMID: 31648317, 27294619, 23958918), especially from a somatic perspective (PMID: 32208489) [PM1]. The variant also demonstrates reduced DNA-binding and CBFβ-binding (PMID: 17290219), as well as impaired erythropoeisis (PMID: 17234761, 21725049) [PS3_moderate], which is in line with computational evidence [PP3]. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3_moderate, PM1, PM2, and PP3. |
NIHR Bioresource Rare Diseases, |
RCV000851801 | SCV000899769 | uncertain significance | Abnormal platelet function | 2019-02-01 | criteria provided, single submitter | research | |
Invitae | RCV001204199 | SCV001375396 | uncertain significance | Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 | 2019-09-26 | 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 variant has been reported to affect RUNX1 protein function (PMID: 12807882, 17234761, 24523240). This variant is also known as p.R135G in the literature. This variant has not been reported in the literature in individuals with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 376022). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 162 of the RUNX1 protein (p.Arg162Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. |
Database of Curated Mutations |
RCV000434358 | SCV000504775 | likely pathogenic | Acute myeloid leukemia | 2014-10-02 | no assertion criteria provided | literature only |