Submissions for variant NM_001972.4(ELANE):c.428G>A (p.Arg143His)

gnomAD frequency: 0.00014  dbSNP: rs200993994

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001719050	SCV000727811	likely benign	not provided	2019-03-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23463630)
Invitae	RCV001796138	SCV000946490	uncertain significance	Cyclical neutropenia; Neutropenia, severe congenital, 1, autosomal dominant	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 143 of the ELANE protein (p.Arg143His). This variant is present in population databases (rs200993994, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cyclic neutropenia (PMID: 23463630). ClinVar contains an entry for this variant (Variation ID: 515631). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ELANE 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.
Genetic Services Laboratory, University of Chicago	RCV001821747	SCV002070096	uncertain significance	not specified	2020-01-13	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ELANE gene demonstrated a sequence change, c.428G>A, in exon 4 that results in an amino acid change, p.Arg143His. This sequence change has been identified in a patient from cohort of patients with a diagnosis of either congenital neutropenia (CN) or cyclic neutropenia (CyN) or myelodysplastic syndrome (MDS) or leukemiadoes (PMID: 23463630) and no patient specific information was provided. It has been described in the gnomAD database with a low population frequency of 0.017% (dbSNP rs200993994). The p.Arg143His change affects a poorly conserved amino acid residue located in a domain of the ELANE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg143His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg143His change remains unknown at this time.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263830	SCV002543418	likely benign	Autoinflammatory syndrome	2021-07-13	criteria provided, single submitter	clinical testing