Submissions for variant NM_001972.4(ELANE):c.568G>A (p.Val190Met)

gnomAD frequency: 0.00004  dbSNP: rs367663236

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000231022	SCV000291945	uncertain significance	not provided	2015-03-31	criteria provided, single submitter	clinical testing	The V190M variant also has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. V190M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues (V186I, R191S, R193Q) have been reported in the Human Gene Mutation Database in association with congenital neutropenia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Genetic Services Laboratory, University of Chicago	RCV001820785	SCV002069951	uncertain significance	not specified	2019-12-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ELANE gene demonstrated a sequence change, c.568G>A, in exon 4 that results in an amino acid change, p.Val190Met. This sequence change does not appear to have been previously described in patients with ELANE-related disorders and has been described in the gnomAD database with a frequency of 0.006% in European populations (dbSNP rs367663236). The p.Val190Met change affects a highly 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.Val190Met substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val190Met change remains unknown at this time.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262842	SCV002543425	likely benign	Autoinflammatory syndrome	2021-09-02	criteria provided, single submitter	clinical testing
Invitae	RCV003765461	SCV004593950	uncertain significance	Cyclical neutropenia; Neutropenia, severe congenital, 1, autosomal dominant	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 190 of the ELANE protein (p.Val190Met). This variant is present in population databases (rs367663236, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ELANE-related conditions. ClinVar contains an entry for this variant (Variation ID: 242296). 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.