Submissions for variant NM_006767.4(LZTR1):c.1750G>A (p.Glu584Lys)

dbSNP: rs369697241

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413012	SCV000492213	uncertain significance	not specified	2016-11-28	criteria provided, single submitter	clinical testing	The E584K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports E584K was observed in 1 of 4404 (0.0227%) alleles from individuals of African American background, indicating it may be a rare variant in this population. E584K 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 conserved across species, yet in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with a RASopathy (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861435	SCV002302364	uncertain significance	not provided	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 584 of the LZTR1 protein (p.Glu584Lys). This variant is present in population databases (rs369697241, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 373604). 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 LZTR1 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.
Ambry Genetics	RCV002411281	SCV002716128	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-05-03	criteria provided, single submitter	clinical testing	The p.E584K variant (also known as c.1750G>A), located in coding exon 15 of the LZTR1 gene, results from a G to A substitution at nucleotide position 1750. The glutamic acid at codon 584 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325198	SCV004031111	uncertain significance	Noonan syndrome 10	2023-08-01	criteria provided, single submitter	clinical testing	The LZTR1 c.1750G>A (p.Glu584Lys) missense variant has a maximum frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have not been performed. This variant has not been reported in individuals with Noonan syndrome or schwannomatosis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.??