Submissions for variant NM_006767.4(LZTR1):c.2263C>T (p.Arg755Trp)

gnomAD frequency: 0.00002  dbSNP: rs141161152

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193026	SCV001361560	uncertain significance	not specified	2024-10-21	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.2263C>T (p.Arg755Trp) results in a non-conservative amino acid change located in the BTB/POZ domain (IPR000210) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2263C>T has been reported in the literature in individuals affected with Nuchal translucency (Ji_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24362817). ClinVar contains an entry for this variant (Variation ID: 928713). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001341224	SCV001535080	uncertain significance	not provided	2025-01-23	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 755 of the LZTR1 protein (p.Arg755Trp). This variant is present in population databases (rs141161152, gnomAD 0.004%). This missense change has been observed in individual(s) with mitral valve prolapse (PMID: 32041611). ClinVar contains an entry for this variant (Variation ID: 928713). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291731	SCV002584664	uncertain significance	Noonan syndrome 10	2022-09-27	criteria provided, single submitter	clinical testing	The LZTR1 c.2263C>T (p.Arg755Trp) missense change has a maximum subpopulation frequency of 0.0080% 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 to our knowledge functional studies have not been performed. This variant has been reported in individual(s) with mitral valve prolapse (PMID: 32041611). To our knowledge, 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.
Ambry Genetics	RCV002447036	SCV002733404	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-06-24	criteria provided, single submitter	clinical testing	The p.R755W variant (also known as c.2263C>T), located in coding exon 19 of the LZTR1 gene, results from a C to T substitution at nucleotide position 2263. The arginine at codon 755 is replaced by tryptophan, an amino acid with dissimilar 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.
Baylor Genetics	RCV003473730	SCV004191215	uncertain significance	LZTR1-related schwannomatosis	2024-02-05	criteria provided, single submitter	clinical testing