ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.743A>C (p.Asn248Thr)

gnomAD frequency: 0.00001  dbSNP: rs747748983
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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 RCV004691997 SCV005196536 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-07-25 reviewed by expert panel curation NM_001754.5(RUNX1):c.743A>C (p.Asn248Thr) is a missense variant. This variant is present in two alleles in the South Asian population at a MAF of 0.0065% in gnomAD v2.1.1. This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (Thrombocytopenia) (PS4_supporting). This missense variant has a REVEL score <0.50 (0.213) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PS4_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000639530 SCV000761105 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2024-10-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 248 of the RUNX1 protein (p.Asn248Thr). This variant is present in population databases (rs747748983, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 532670). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
PreventionGenetics, part of Exact Sciences RCV004742550 SCV005353093 uncertain significance RUNX1-related disorder 2024-06-13 no assertion criteria provided clinical testing The RUNX1 c.743A>C variant is predicted to result in the amino acid substitution p.Asn248Thr. This variant has been reported in the literature in one individual with thrombocytopenia, intellectual disability and dysmorphic features (Liu et al. 2023. PubMed ID: 36819173). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant has been classified as a variant of uncertain significance by one laboratory in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/532670/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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