Submissions for variant NM_006767.4(LZTR1):c.851G>A (p.Arg284His)

dbSNP: rs768361273

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001228996	SCV001401426	likely pathogenic	not provided	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 284 of the LZTR1 protein (p.Arg284His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of Noonan syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 956230). 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%. This variant disrupts the p.Arg284 amino acid residue in LZTR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25335493, 25795793, 29346770, 30481304, 33792302). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005236700	SCV002500275	likely pathogenic	RASopathy	2024-12-13	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.851G>A (p.Arg284His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. A different pathogenic amino acid change at the same codon, p.Arg284Cys has been observed in affected individuals supporting a critical relevance of this residue to LZTR1 protein function (PMID 30664951). The variant allele was found at a frequency of 3.1e-06 in 1603628 control chromosomes. c.851G>A has been reported in the literature in individuals affected with features of Noonan Syndrome (Lin_2024) and also via internal testing at our partner laboratory. These data indicate that the variant is likely to be associated with disease. 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: 38178226). ClinVar contains an entry for this variant (Variation ID: 956230). To our knowledge, this variant has not been reported in individuals with AR Noonan Syndrome or AD Schwannomatosis. Based on the evidence outlined above, this variant is likely pathogenic for AD Noonan Syndrome.
Ambry Genetics	RCV002447149	SCV002681560	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-07-31	criteria provided, single submitter	clinical testing	The p.R284H variant (also known as c.851G>A), located in coding exon 9 of the LZTR1 gene, results from a G to A substitution at nucleotide position 851. The arginine at codon 284 is replaced by histidine, 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 deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV001228996	SCV003803356	pathogenic	not provided	2025-01-17	criteria provided, single submitter	clinical testing	Identified in a fetus with a congenital heart defect in published literature (PMID: 38178226); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30664951, 38178226)
Centre for Human Genetics	RCV003449721	SCV005200524	uncertain significance	Noonan syndrome 1		criteria provided, single submitter	clinical testing	The c.851G>A variant (p.R284H) found in coding exon 9 of the LZTR1 gene, substitutes arginine with histidine at codon 284. This position is highly conserved among vertebrates. In silico predictions suggest that this change could be harmful. However, due to lack of experimental evidence demonstrating its impact on protein function, the clinical significance of this variant is currently uncertain.
Molecular Genetics, Centre for Human Genetics	RCV003449721	SCV004190073	uncertain significance	Noonan syndrome 1		no assertion criteria provided	clinical testing