Submissions for variant NM_001754.5(RUNX1):c.414A>C (p.Glu138Asp)

dbSNP: rs771823558

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004734005	SCV005367746	uncertain significance	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-09-25	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.414A>C (p.Glu138Asp) is a variant which affects a residue within the Runt Homology domain (AA89-294) but does not impact a residue which has been established as a hotspot (PM1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071415	SCV001236719	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2022-04-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 864271). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 138 of the RUNX1 protein (p.Glu138Asp).
CeGaT Center for Human Genetics Tuebingen	RCV001312003	SCV001502413	uncertain significance	not provided	2020-09-01	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001312003	SCV005198089	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004960434	SCV005495297	uncertain significance	Inborn genetic diseases	2024-11-24	criteria provided, single submitter	clinical testing	The p.E138D variant (also known as c.414A>C), located in coding exon 4 of the RUNX1 gene, results from an A to C substitution at nucleotide position 414. The glutamic acid at codon 138 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV001312003	SCV005688163	uncertain significance	not provided	2024-07-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in any cases, but was observed in unaffected controls from a melanoma study (PMID: 29641532); This variant is associated with the following publications: (PMID: 29641532)