Submissions for variant NM_006767.4(LZTR1):c.850C>T (p.Arg284Cys)

gnomAD frequency: 0.00001  dbSNP: rs797045165

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658480	SCV000778847	pathogenic	not provided	2021-11-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant results in the upregulation of RAS-MAPK signaling (Motta et al., 2019); 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, 29346770, 25795793, 27942422, 26446362, 25335493, 30481304)
Fulgent Genetics, Fulgent Genetics	RCV000763073	SCV000893583	pathogenic	Schwannomatosis 2; Noonan syndrome 10	2018-10-31	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000191028	SCV000996259	pathogenic	Noonan syndrome 10	2019-03-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in six related individuals with autosomal dominant Noonan Syndrome (PMID: 25795793) and as an apparently de novo change in an individual with schwannomatosis (PMID: 25335493). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. This variant has been classified as a de novo pathogenic variant for Noonan syndrome in ClinVar (Variation ID: 209089). In-silico analyses support a damaging effect of the c.850C>T (p.Arg284Cys) variant on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.850C>T (p.Arg284Cys) variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000658480	SCV002141150	pathogenic	not provided	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 284 of the LZTR1 protein (p.Arg284Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and/or schwannomatosis (PMID: 25335493, 25795793, 30664951). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209089). 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%. Experimental studies have shown that this missense change affects LZTR1 function (PMID: 30481304). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000191028	SCV002580990	pathogenic	Noonan syndrome 10	2022-09-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444774	SCV002681537	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-11-01	criteria provided, single submitter	clinical testing	The p.R284C pathogenic mutation (also known as c.850C>T), located in coding exon 9 of the LZTR1 gene, results from a C to T substitution at nucleotide position 850. The arginine at codon 284 is replaced by cysteine, an amino acid with highly dissimilar properties. In one large Brazilian family, this alteration arose de novo in an individual affected with Noonan syndrome and segregated with disease in an autosomal dominant manner in that patient's offspring (Yamamoto GL et al. J. Med. Genet., 2015 Jun;52:413-21). This mutation has been reported in the literature in other individuals with autosomal dominant Noonan syndrome (Jacquinet A Eur J Med Genet 2020 Jan;63(1):103617; Bertola DR et al. Am J Med Genet C Semin Med Genet 2020 12;184(4):896-911). This variant has also been reported in an individual with schwannomatosis (Paganini I et al. Eur. J. Hum. Genet., 2015 Jul;23:963-8). Functional studies indicate that this alteration enhances RAS-MAPK signaling (Motta M et al. Hum. Mol. Genet., 2019 03;28:1007-1022). Based on the supporting evidence, this variant is pathogenic for autosomal dominant Noonan syndrome; however, the association of this alteration with an increased risk of LZTR1-related schwannomatosis (SWN) is unknown.
CeGaT Center for Human Genetics Tuebingen	RCV000658480	SCV004011380	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	LZTR1: PS2, PM2, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting
OMIM	RCV000191028	SCV000246008	pathogenic	Noonan syndrome 10	2015-06-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004530087	SCV004714432	pathogenic	LZTR1-related disorder	2024-07-09	no assertion criteria provided	clinical testing	The LZTR1 c.850C>T variant is predicted to result in the amino acid substitution p.Arg284Cys. This variant has been reported to be de novo and to segregate with disease in multiple individuals with Noonan syndrome (Yamamoto et al. 2015. PubMed ID: 25795793; Motta et al. 2018. PubMed ID: 30481304; Jacquinet et al. 2020. PubMed ID: 30664951). This variant has also been reported as de novo in multiple individuals with autism spectrum disorders (Table S1, Takata et al. 2018. PubMed ID: 29346770; Table S20, Fu et al. 2022. PubMed ID: 35982160; Table S1, Zhou et al. 2022. PubMed ID: 35982159). Additionally, this variant has been reported as de novo in an individual with schwannomatosis (Paganini et al. 2015. PubMed ID: 25335493). Functional studies found this variant results in enhanced EGF-dependent ERK1/2 phosphorylation (Motta et al. 2018. PubMed ID: 30481304). This variant has not been reported in a large population database, indicating this variant is rare; however, the quality of this data is questionable and should be treated with caution. This variant is interpreted as pathogenic.