Submissions for variant NM_001972.4(ELANE):c.628G>A (p.Gly210Arg)

gnomAD frequency: 0.00001  dbSNP: rs140880838

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255959	SCV000321598	pathogenic	not provided	2014-04-08	criteria provided, single submitter	clinical testing	To our knowledge, the G210R substitution has not been published as a mutation, nor has it been reported as a benign polymorphism. The G210R mutation was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. G210R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the peptidase S1 domain that is moderately conserved across species. In silico analysis is inconsistent in its predictions as to whether or not this substitution is damaging to the protein structure/function. Missense mutations in the same residue (G210V, G210W) have been reported in the Human Gene Mutation Database in association with congenital neutropenia (Stenson et al., 2009), supporting the functional importance of this region of the protein. Therefore, we consider G210R a mutation and its presence consistent with a diagnosis of ELANE-related neutropenia.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765567	SCV004585967	uncertain significance	Cyclical neutropenia; Neutropenia, severe congenital, 1, autosomal dominant	2024-02-22	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 210 of the ELANE protein (p.Gly210Arg). This variant is present in population databases (rs140880838, gnomAD 0.02%). This missense change has been observed in individual(s) with ELANE-related conditions (PMID: 28881492). ClinVar contains an entry for this variant (Variation ID: 265119). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ELANE protein function with a negative predictive value of 80%. This variant disrupts the p.Gly210 amino acid residue in ELANE. Other variant(s) that disrupt this residue have been observed in individuals with ELANE-related conditions (PMID: 11001877, 19775295), which suggests that this may be a clinically significant amino acid residue. 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.