Submissions for variant NM_004364.5(CEBPA):c.364G>C (p.Gly122Arg)

gnomAD frequency: 0.00029  dbSNP: rs1013724730

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631419	SCV000752492	uncertain significance	Acute myeloid leukemia	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 122 of the CEBPA protein (p.Gly122Arg). This variant is present in population databases (no rsID available, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CEBPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 526801). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CEBPA protein function with a negative predictive value of 80%. 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.
Genetic Services Laboratory, University of Chicago	RCV001821787	SCV002065937	uncertain significance	not specified	2020-08-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CEBPA gene demonstrated a sequence change, c.364G>C, in exon 1 that results in an amino acid change, p.Gly122Arg. This sequence change does not appear to have been previously described in patients with CEBPA-related disorders and has been described in the gnomAD database with a frequency of 0.086% in the African sub-population (dbSNP rs1013724730). The p.Gly122Arg change affects a poorly conserved amino acid residue located in a domain of the CEBPA protein that is known to be functional. The p.Gly122Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly122Arg change remains unknown at this time.
Sema4, Sema4	RCV002256421	SCV002531745	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-30	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000631419	SCV002789794	uncertain significance	Acute myeloid leukemia	2022-04-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002509478	SCV002818933	uncertain significance	not provided	2022-07-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Revvity Omics, Revvity	RCV000631419	SCV003831546	uncertain significance	Acute myeloid leukemia	2019-11-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003403447	SCV004119088	uncertain significance	CEBPA-related disorder	2022-09-13	criteria provided, single submitter	clinical testing	The CEBPA c.364G>C variant is predicted to result in the amino acid substitution p.Gly122Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.086% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-33792957-C-G), and it is documented as a variant of uncertain significance by multiple labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/526801/evidence/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000631419	SCV004214814	uncertain significance	Acute myeloid leukemia	2023-05-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004975733	SCV005558674	likely benign	Inborn genetic diseases	2024-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.