Submissions for variant NM_006767.4(LZTR1):c.1610G>A (p.Arg537Gln)

gnomAD frequency: 0.00003  dbSNP: rs769150226

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522570	SCV000620234	uncertain significance	not provided	2017-08-18	criteria provided, single submitter	clinical testing	The R537Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R537Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R537Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001644623	SCV001852722	uncertain significance	LZTR1-related schwannomatosis	2021-04-17	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 14 of the LZTR1 gene that results in the amino acid substitution of Glutamine for Arginine at codon 537 was detected. The observed variant c.1610G>A (p.Arg537Gln) has a minor allele frequency of 0.006%, in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
Ambry Genetics	RCV002395254	SCV002703133	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-10-03	criteria provided, single submitter	clinical testing	The p.R537Q variant (also known as c.1610G>A), located in coding exon 14 of the LZTR1 gene, results from a G to A substitution at nucleotide position 1610. The arginine at codon 537 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000522570	SCV004452930	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 537 of the LZTR1 protein (p.Arg537Gln). This variant is present in population databases (rs769150226, gnomAD 0.01%). 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: 451516). 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 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.