VCV000209089.29 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 209089 Accession: VCV000209089.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q11.21 22: 20991686 (GRCh38) [ NCBI UCSC ] 22: 21345975 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 9, 2018	Oct 20, 2024	Nov 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006767.4:c.850C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006758.2:p.Arg284Cys	missense
NC_000022.11:g.20991686C>T
NC_000022.10:g.21345975C>T
NG_034193.1:g.14418C>T
LRG_989:g.14418C>T
LRG_989t1:c.850C>T	LRG_989p1:p.Arg284Cys
	Q8N653:p.Arg284Cys

... more HGVS ... less HGVS

Protein change

R284C

Other names

Canonical SPDI

NC_000022.11:20991685:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA204980 UniProtKB: Q8N653#VAR_075660 OMIM: 600574.0007 dbSNP: rs797045165 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LZTR1		-	-	GRCh38 GRCh37	3176	3687

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Noonan syndrome 10	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 6, 2022	RCV000191028.8
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 11, 2023	RCV000658480.21
Noonan syndrome 10 Schwannomatosis 2	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763073.3
Cardiovascular phenotype Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Nov 1, 2023	RCV002444774.4
LZTR1-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 9, 2024	RCV004530087.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schwannomatosis 2 Noonan syndrome 10 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893583.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Mar 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOONAN SYNDROME 10 Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996259.1 First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (Nov 12, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000778847.4 First in ClinVar: Jul 09, 2018 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Sep 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 10 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580990.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PP1_STR, PS4_MOD, PM6, PS3_SUP, PM2_SUP, PP3	Number of individuals with the variant: 1 Sex: female
Pathogenic (Nov 11, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002141150.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 25335493‚ 25795793‚ 30664951‚ 30481304 Comment: 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 … (more) 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. (less)
Pathogenic (Nov 01, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Hereditary cancer-predisposing syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002681537.3 First in ClinVar: Nov 29, 2022 Last updated: Jun 09, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (Jun 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004011380.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: LZTR1: PS2, PM2, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (Jun 01, 2015)	no assertion criteria provided Method: literature only	NOONAN SYNDROME 10 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000246008.3 First in ClinVar: Sep 29, 2015 Last updated: Nov 06, 2020	Publications: PubMed (2) PubMed: 25795793‚ 30664951 Comment on evidence: In 6 members of a Brazilian family (Br-F4) with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified a heterozygous c.850C-T transition (c.850C-T, NM_006767.3) in … (more) In 6 members of a Brazilian family (Br-F4) with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified a heterozygous c.850C-T transition (c.850C-T, NM_006767.3) in exon 9 of the LZTR1 gene, resulting in an arg284-to-cys (R284C) substitution in the KT4 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 609 Brazilian controls. Functional studies of the variant were not performed. Jacquinet et al. (2020) reported a 26-year-old male with NS10 who had inherited the R284C mutation from his affected mother. He developed an oligoastrocytoma at age 22 years that was resected but recurred as a ganglioblastoma at age 26 years. The patient had been treated with growth hormone for short stature between ages 15 and 17 years. Facial features of Noonan syndrome, kyphoscoliosis with gibbus, and pectus excavatum were present; cardiac malformation, cardiomyopathy, and hyperkeratosis were absent. Jacquinet et al. (2020) hypothesized that gliomas are a possible complication of LZTR1-related Noonan syndrome, and stated that their report supported a possible link between occurrence of a cerebral tumor in Noonan syndrome and treatment with growth hormone. In addition to the R284C mutation, the patient and his mother carried a mutation resulting in Charcot-Marie-Tooth disease type 1A (CMT1A; 601097). (less)
Pathogenic (Jul 09, 2024)	no assertion criteria provided Method: clinical testing	LZTR1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004714432.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Oligo-astrocytoma in LZTR1-related Noonan syndrome.	Jacquinet A	European journal of medical genetics	2020	PMID: 30664951
Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling.	Motta M	Human molecular genetics	2019	PMID: 30481304
Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.	Yamamoto GL	Journal of medical genetics	2015	PMID: 25795793
Expanding the mutational spectrum of LZTR1 in schwannomatosis.	Paganini I	European journal of human genetics : EJHG	2015	PMID: 25335493

Text-mined citations for rs797045165 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs797045165 ...