Submissions for variant NM_001972.4(ELANE):c.217G>A (p.Ala73Thr)

gnomAD frequency: 0.00011  dbSNP: rs201421847

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000229821	SCV000291939	uncertain significance	not provided	2014-08-01	criteria provided, single submitter	clinical testing	The A73T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A73T variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A73T variant 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 that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Missense mutations in nearby residues (C71R, C71S, C71Y, C71F, V72E, V72G, R78H, V80G, R81P, V82M) have been reported in the Human Gene Mutation Database in association with ELANE-related disorders (Stenson et al., 2009), 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.
Invitae	RCV001795379	SCV001211729	uncertain significance	Cyclical neutropenia; Neutropenia, severe congenital, 1, autosomal dominant	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the ELANE protein (p.Ala73Thr). This variant is present in population databases (rs201421847, gnomAD 0.03%), 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 ELANE-related conditions. ClinVar contains an entry for this variant (Variation ID: 242290). 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262840	SCV002543409	uncertain significance	Autoinflammatory syndrome	2022-03-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001795379	SCV002799742	uncertain significance	Cyclical neutropenia; Neutropenia, severe congenital, 1, autosomal dominant	2022-04-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020901	SCV004863113	likely benign	Inborn genetic diseases	2023-10-27	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.