Submissions for variant NM_006767.4(LZTR1):c.1303C>T (p.Arg435Trp)

gnomAD frequency: 0.00008  dbSNP: rs369722558

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681416	SCV000808879	uncertain significance	not provided	2024-06-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25795793)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000681416	SCV002132677	uncertain significance	not provided	2024-02-01	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 435 of the LZTR1 protein (p.Arg435Trp). This variant is present in population databases (rs369722558, 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: 561957). 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.
Ambry Genetics	RCV002386155	SCV002691197	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-08-02	criteria provided, single submitter	clinical testing	The p.R435W variant (also known as c.1303C>T), located in coding exon 12 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1303. The arginine at codon 435 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV003320365	SCV004024510	uncertain significance	Noonan syndrome 10	2023-06-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003465551	SCV004191254	uncertain significance	Schwannomatosis 2	2024-03-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000681416	SCV004225569	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV003886429	SCV004704505	uncertain significance	Noonan syndrome 2	2023-07-11	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PP3_MOD
Molecular Genetics, Centre for Human Genetics	RCV003453399	SCV004190074	uncertain significance	Noonan syndrome 1		no assertion criteria provided	clinical testing