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	uncertain significance	not provided	2023-01-20	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.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. 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. ClinVar contains an entry for this variant (Variation ID: 956230). This missense change has been observed in individual(s) with a clinical diagnosis of Noonan syndrome (Invitae). 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 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222681	SCV002500275	uncertain significance	not specified	2022-03-09	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. The variant allele was found at a frequency of 8.7e-06 in 230502 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.851G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Another variant affecting the same residue c.850C > T/p.Arg284Cys have been observed in an individual affected with Noonan Syndrome (Jacquinet_2020). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002447149	SCV002681560	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-11-13	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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001228996	SCV003803356	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); 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 in germline to our knowledge; This variant is associated with the following publications: (PMID: 30664951, 25335493, 25795793)
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