Submissions for variant NM_006767.4(LZTR1):c.1432C>T (p.Arg478Trp)

gnomAD frequency: 0.00001  dbSNP: rs150365548

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001996996	SCV002227378	uncertain significance	not provided	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 478 of the LZTR1 protein (p.Arg478Trp). This variant is present in population databases (rs150365548, gnomAD 0.006%). 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: 1447962). 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	RCV002388920	SCV002701062	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-10-30	criteria provided, single submitter	clinical testing	The p.R478W variant (also known as c.1432C>T), located in coding exon 13 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1432. The arginine at codon 478 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been observed in a patient with reported Noonan syndrome; however, complete clinical information on this individual was not provided (Lazzaro G et al. Mol Genet Genomic Med, 2020 04;8:e1069). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005054391	SCV005688749	uncertain significance	Noonan syndrome 2	2023-11-27	criteria provided, single submitter	clinical testing	The LZTR1 c.1432C>T (p.Arg478Trp) variant has been reported in the literature in an individual with a clinical diagnosis of Noonan syndrome with mild conductive hearing loss (Lazzaro G et al., PMID: 32059087). This variant has been reported in the ClinVar database as a germline variant of uncertain significance by two submitters. This variant is only observed on 9/241,152 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in an alpha helix in the BTB domain and changes a positively charged arginine to a non-polar tryptophan, but computational predictors suggest that the variant does not impact LZTR1 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.