Submissions for variant NM_006767.4(LZTR1):c.370G>A (p.Val124Ile)

dbSNP: rs759568976

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002353034	SCV002624938	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-04-22	criteria provided, single submitter	clinical testing	The p.V124I variant (also known as c.370G>A), located in coding exon 4 of the LZTR1 gene, results from a G to A substitution at nucleotide position 370. The valine at codon 124 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly 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	RCV003094316	SCV003010480	uncertain significance	not provided	2024-04-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 124 of the LZTR1 protein (p.Val124Ile). This variant is present in population databases (no rsID available, gnomAD no frequency). 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: 1734186). 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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV003234590	SCV003932613	uncertain significance	Noonan syndrome 10	2023-06-14	criteria provided, single submitter	clinical testing	A heterozygous missense variant in exon 4 of the LZTR1 gene that results in the amino acid substitution of Isoleucine for Valine at codon 124 (p.Val124Ile) was detected. The p.Val124Ile variant has not been reported in the 1000 genomes, gnomAD (v3.1) and gnomdAD (v2) databases and has a minor allele frequency of 0.001% in the topmed databases. The in-silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT and LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
Baylor Genetics	RCV004572259	SCV005060639	uncertain significance	LZTR1-related schwannomatosis	2024-02-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003094316	SCV005331389	uncertain significance	not provided	2024-08-01	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005051960	SCV005685407	uncertain significance	Noonan syndrome 2; Noonan syndrome 10	2024-05-21	criteria provided, single submitter	clinical testing	An LZTR1 c.370G>A (p.Val124Ile) variant was identified at a near heterozygous allelic fraction of 46.6%, a frequency which may be consistent with germline origin. This variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a germline variant of uncertain significance by three submitters (ClinVar ID: 1734186). This variant is observed on 16/1,614,074 alleles in the general population (gnomAD v.4.1.0). Computational predictors are uncertain as to the impact of this variant on 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.