Submissions for variant NM_006767.4(LZTR1):c.508C>T (p.Arg170Trp)

gnomAD frequency: 0.00003  dbSNP: rs757502214

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001763326	SCV001990737	uncertain significance	not provided	2020-12-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with another LZTR1 variant on the same allele (in cis), both in the homozygous state in an individual with features of Noonan syndrome (Johnston 2018); This variant is associated with the following publications: (PMID: 29469822)
Baylor Genetics	RCV001788834	SCV002030162	uncertain significance	Noonan syndrome 10	2021-09-28	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002334669	SCV002641904	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-04-28	criteria provided, single submitter	clinical testing	The p.R170W variant (also known as c.508C>T), located in coding exon 5 of the LZTR1 gene, results from a C to T substitution at nucleotide position 508. The arginine at codon 170 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported as homozygous in a Syrian child with Noonan syndrome born to cansanguineous, unaffected parents and was not present in the biallelic state in three unaffected siblings. Of note, p.R170W occurred in cis with LZTR1 p.I205T and authors state they cannot exclude the possibility that neither variant would be pathogenic alone (Johnston JJ et al. Genet Med, 2018 10;20:1175-1185). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001763326	SCV003522378	uncertain significance	not provided	2022-10-26	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Arg170 amino acid residue in LZTR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25480913, 30481304). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 1308414). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 29469822). This variant is present in population databases (rs757502214, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 170 of the LZTR1 protein (p.Arg170Trp).
Baylor Genetics	RCV003470885	SCV004191245	uncertain significance	Schwannomatosis 2	2023-11-14	criteria provided, single submitter	clinical testing