VCV000561716.33 - ClinVar

NM_006767.4(LZTR1):c.848G>A (p.Arg283Gln)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Likely Pathogenic

for RASopathy

Classification is based on the expert panel submission

Dec 2024 by ClinGen RASopathy Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Uncertain significance

This classification is based on the single submission received

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Variant Details

Identifiers

NM_006767.4(LZTR1):c.848G>A (p.Arg283Gln)

Variation ID: 561716 Accession: VCV000561716.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q11.21 22: 20991684 (GRCh38) [ NCBI UCSC ] 22: 21345973 (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	Sep 22, 2018	Mar 7, 2026	Dec 3, 2024
Somatic - Oncogenicity	Jan 3, 2026	Jan 3, 2026	Dec 29, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_006767.4:c.848G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006758.2:p.Arg283Gln	missense
NC_000022.11:g.20991684G>A
NC_000022.10:g.21345973G>A
NG_034193.1:g.14416G>A
LRG_989:g.14416G>A
LRG_989t1:c.848G>A	LRG_989p1:p.Arg283Gln

... more HGVS ... less HGVS

Protein change

R283Q

Other names

NM_006767.4(LZTR1):c.848G>A

Canonical SPDI

NC_000022.11:20991683:G:A

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: CA410781238 dbSNP: rs1223430276 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	4586	5181

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.
not provided	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Dec 20, 2025	RCV000681082.27
Noonan syndrome 10	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 21, 2018	RCV000761304.16
Noonan syndrome and Noonan-related syndrome	Likely pathogenic (1)	criteria provided, single submitter	Dec 8, 2022	RCV001813545.13
RASopathy	Likely pathogenic (2)	reviewed by expert panel	Dec 3, 2024	RCV002233108.10
Noonan syndrome 1	Likely pathogenic (1)	no assertion criteria provided	-	RCV003151134.8
LZTR1-related disorder	Pathogenic (2)	criteria provided, single submitter	Sep 12, 2024	RCV004535698.3
Male infertility with azoospermia or oligozoospermia due to single gene mutation	Pathogenic (1)	criteria provided, single submitter	Dec 1, 2023	RCV003991581.2
LZTR1-related schwannomatosis	Pathogenic (1)	criteria provided, single submitter	Nov 27, 2023	RCV004568578.1
Cardiovascular phenotype Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Oct 28, 2024	RCV004993935.1

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.	Expand all rows Collapse all rows 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.
Likely Pathogenic (Dec 03, 2024) C Contributing to aggregate classification	reviewed by expert panel (ClinGen RASopathy ACMG Specifications LZTR1 V1.3.0)	RASopathy (Autosomal dominant inheritance)	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV006059799.1 First in ClinVar: May 03, 2025 Last updated: May 03, 2025	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c8222db2-1fa0-4817-b2bb-713739454635 Comment: show The NM_006767.4:c.848G>A variant in LZTR1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 283 (p.Arg283Gln). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.609, which is neither above nor below the thresholds predicting a damaging or benign impact on LZTR1 function. This variant has been reported in 5 probands with RASopathy (PS4_Moderate; PMID: 30368668, SCV000808536.4, GeneDx). This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with RASopathy (PS2; PMID: 30368668, SCV000808536.4, GeneDx). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS4_Moderate, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Likely pathogenic (Nov 21, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Noonan syndrome 10	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota Accession: SCV000891281.1 First in ClinVar: Mar 24, 2019 Last updated: Mar 24, 2019	Publications: PubMed (3) PubMed: 16356934‚ 25795793‚ 30368668 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Likely pathogenic (Mar 19, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Noonan syndrome 10	Baylor Genetics Accession: SCV001526201.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: show This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. (less) Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes

Likely pathogenic (Apr 07, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	RASopathy	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001448329.2 First in ClinVar: Dec 07, 2020 Last updated: May 16, 2022	Publications: PubMed (3) PubMed: 30368668‚ 33258288‚ 33587123 Comment: show Variant summary: LZTR1 c.848G>A (p.Arg283Gln) results in a conservative amino acid change located in the Kelch repeat type 1 domain (IPR006652) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230510 control chromosomes (gnomAD). c.848G>A has been reported in the literature in individuals affected with Noonan Syndrome, including two individuals were the variant arose de novo (Umeki_2019, Quaio_2020) and one individual via maternal inheritance (Maron_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Umeki_2019). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 15, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000808536.4 First in ClinVar: Sep 22, 2018 Last updated: Mar 04, 2023	Comment: show Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30368668, 33258288, 33792302) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Nov 27, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	LZTR1-related schwannomatosis	Baylor Genetics Accession: SCV005060701.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Dec 08, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Noonan syndrome and Noonan-related syndrome	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060780.2 First in ClinVar: Jan 20, 2022 Last updated: Oct 08, 2024	Comment: show This missense variant results in a change from arginine to glutamine at amino acid position 283. It has been reported previously in individuals with Noonan syndrome (PMIDs: 30368668, 33587123) or neurological anomaly (precise phenotype not specified – PMID: 33258288). This variant was reported to have occurred de novo in at least one individual. This variant is observed at an allele frequency of 0.000062% in population controls of the Genome Aggregation Database (gnomAD). In silico prediction programs predict this variant to impact protein function. Based on the evidence above, this variant is classified as likely pathogenic (ACMG criteria - PS4_Moderate, PM6, PP3, PP5). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

pathogenic (Aug 22, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics Criteria)	not provided	Athena Diagnostics Accession: SCV002817313.2 First in ClinVar: Dec 31, 2022 Last updated: Oct 08, 2024	Publications: PubMed (6) PubMed: 30368668‚ 30859559‚ 33258288‚ 33587123‚ 35253369‚ 35979676 Comment: show The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. This variant appears to occur de novo in one individual with clinical features associated with this gene. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Oct 28, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	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.	Ambry Genetics Accession: SCV005616231.1 First in ClinVar: Jan 13, 2025 Last updated: Jan 13, 2025	Publications: PubMed (4) PubMed: 35253369‚ 35840934‚ 35979676‚ 38654924 Comment: show The p.R283Q variant (also known as c.848G>A), located in coding exon 9 of the LZTR1 gene, results from a G to A substitution at nucleotide position 848. The arginine at codon 283 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple probands with features consistent with autosomal dominant Noonan syndrome, including at least 2 individuals with reported de novo variants (Verberne EA et al. Am J Med Genet A, 2022 Jun;188:1777-1791; Swarts JW et al. Am J Med Genet A, 2022 Nov;188:3242-3261; Farncombe KM et al. BMC Med Genomics, 2022 Jul;15:160; Juchnewitsch AG et al. Front Endocrinol (Lausanne), 2024 Apr;15:1312357). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is likely pathogenic for autosomal dominant Noonan syndrome; however, the association of this alteration with an increased risk of LZTR1-related schwannomatosis (SWN) is unknown. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Sep 12, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	LZTR1-related disorder	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV005873953.1 First in ClinVar: Mar 11, 2025 Last updated: Mar 11, 2025	Comment: show PS4, PM2, PM6_Strong, PP3 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Dec 01, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Gelb et al. (Genet Med. 2018))	Male infertility with azoospermia or oligozoospermia due to single gene mutation (Autosomal dominant inheritance)	Laan Lab, Human Genetics Research Group, University of Tartu Accession: SCV004231717.2 First in ClinVar: Apr 15, 2024 Last updated: Apr 13, 2025	Publications: DOI: 10.3389/fendo.2024.1312357 DOI: 10.3389/fendo.2024.1312357 Observation: 1 Collection method: research Allele origin: germline Affected status: yes more Observation 1 Collection method: research Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Zygosity: 1 Single Heterozygote Sex: male Platform type: exome sequencing

Likely pathogenic (Jul 18, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Revvity Omics, Revvity Accession: SCV003832268.3 First in ClinVar: Mar 04, 2023 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Dec 20, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003254428.4 First in ClinVar: Feb 07, 2023 Last updated: Mar 07, 2026	Publications: PubMed (2) PubMed: 30368668‚ 33258288 Comment: show This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 283 of the LZTR1 protein (p.Arg283Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 30368668, 33258288; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 561716). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LZTR1 function (PMID: 30368668). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics, Academic Medical Center Study: VKGL Data-share Consensus Accession: SCV001917340.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Study: VKGL Data-share Consensus Accession: SCV001956355.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Noonan syndrome 1	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV003840171.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Observation: 1 Collection method: research Allele origin: unknown Affected status: yes more Observation 1 Collection method: research Allele origin: unknown Affected status: yes Number of individuals with the variant: 1

Likely pathogenic (Nov 21, 2023) N Not contributing to aggregate classification	no assertion criteria provided	LZTR1-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004106725.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: show The LZTR1 c.848G>A variant is predicted to result in the amino acid substitution p.Arg283Gln. This variant was reported de novo in two individuals with Noonan syndrome (Umeki et al. 2019. PubMed ID: 30368668; supplementary material, Quaio et al. 2020. PubMed ID: 33258288). This variant was also reported as maternally-inherited in an individual with Noonan syndrome (eTable 2, Maron et al. 2021. PubMed ID: 33587123). In vitro functional studies showed that this variant does not induce the activation of ERK- or ELK-mediated transactivation (Figure S2, Umeki et al. 2019. PubMed ID: 30368668). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

The NM_006767.4:c.848G>A variant in LZTR1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 283 (p.Arg283Gln). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.609, which is neither above nor below the thresholds predicting a damaging or benign impact on LZTR1 function. This variant has been reported in 5 probands with RASopathy (PS4_Moderate; PMID: 30368668, SCV000808536.4, GeneDx). This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with RASopathy (PS2; PMID: 30368668, SCV000808536.4, GeneDx). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS4_Moderate, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024)

Comment:

Variant summary: LZTR1 c.848G>A (p.Arg283Gln) results in a conservative amino acid change located in the Kelch repeat type 1 domain (IPR006652) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230510 control chromosomes (gnomAD). c.848G>A has been reported in the literature in individuals affected with Noonan Syndrome, including two individuals were the variant arose de novo (Umeki_2019, Quaio_2020) and one individual via maternal inheritance (Maron_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Umeki_2019). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30368668, 33258288, 33792302)

Comment:

This missense variant results in a change from arginine to glutamine at amino acid position 283. It has been reported previously in individuals with Noonan syndrome (PMIDs: 30368668, 33587123) or neurological anomaly (precise phenotype not specified – PMID: 33258288). This variant was reported to have occurred de novo in at least one individual. This variant is observed at an allele frequency of 0.000062% in population controls of the Genome Aggregation Database (gnomAD). In silico prediction programs predict this variant to impact protein function. Based on the evidence above, this variant is classified as likely pathogenic (ACMG criteria - PS4_Moderate, PM6, PP3, PP5).

Comment:

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. This variant appears to occur de novo in one individual with clinical features associated with this gene.

Comment:

The p.R283Q variant (also known as c.848G>A), located in coding exon 9 of the LZTR1 gene, results from a G to A substitution at nucleotide position 848. The arginine at codon 283 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple probands with features consistent with autosomal dominant Noonan syndrome, including at least 2 individuals with reported de novo variants (Verberne EA et al. Am J Med Genet A, 2022 Jun;188:1777-1791; Swarts JW et al. Am J Med Genet A, 2022 Nov;188:3242-3261; Farncombe KM et al. BMC Med Genomics, 2022 Jul;15:160; Juchnewitsch AG et al. Front Endocrinol (Lausanne), 2024 Apr;15:1312357). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is likely pathogenic for autosomal dominant Noonan syndrome; however, the association of this alteration with an increased risk of LZTR1-related schwannomatosis (SWN) is unknown.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 283 of the LZTR1 protein (p.Arg283Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 30368668, 33258288; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 561716). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LZTR1 function (PMID: 30368668). For these reasons, this variant has been classified as Pathogenic.

Comment:

The LZTR1 c.848G>A variant is predicted to result in the amino acid substitution p.Arg283Gln. This variant was reported de novo in two individuals with Noonan syndrome (Umeki et al. 2019. PubMed ID: 30368668; supplementary material, Quaio et al. 2020. PubMed ID: 33258288). This variant was also reported as maternally-inherited in an individual with Noonan syndrome (eTable 2, Maron et al. 2021. PubMed ID: 33587123). In vitro functional studies showed that this variant does not induce the activation of ERK- or ELK-mediated transactivation (Figure S2, Umeki et al. 2019. PubMed ID: 30368668). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Undiagnosed RASopathies in infertile men.	Juchnewitsch AG	Frontiers in endocrinology	2024	PMID: 38654924
Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study.	Swarts JW	American journal of medical genetics. Part A	2022	PMID: 35979676
LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis.	Farncombe KM	BMC medical genomics	2022	PMID: 35840934
Genetic care in geographically isolated small island communities: 8 years of experience in the Dutch Caribbean.	Verberne EA	American journal of medical genetics. Part A	2022	PMID: 35253369
Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study.	Maron JL	JAMA pediatrics	2021	PMID: 33587123
Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.	Quaio CRDC	American journal of medical genetics. Part C, Seminars in medical genetics	2020	PMID: 33258288
Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.	Pagnamenta AT	Clinical genetics	2019	PMID: 30859559
Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.	Umeki I	Human genetics	2019	PMID: 30368668
Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.	Yamamoto GL	Journal of medical genetics	2015	PMID: 25795793
The BTB-kelch protein LZTR-1 is a novel Golgi protein that is degraded upon induction of apoptosis.	Nacak TG	The Journal of biological chemistry	2006	PMID: 16356934
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c8222db2-1fa0-4817-b2bb-713739454635	-	-	-	-
-	-	-	-	DOI: 10.3389/fendo.2024.1312357
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Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Uncertain significance criteria provided, single submitter	Dec 29, 2025	RCV006273982.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity 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)	Tumor type Help The tumor type 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.	Expand all rows Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Uncertain significance (Dec 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)	Neoplasm	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV007129470.1 First In ClinVar: Jan 03, 2026 Last updated: Jan 03, 2026	Publications: PubMed (1) PubMed: 30368668 Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Comment:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.	Umeki I	Human genetics	2019	PMID: 30368668

Text-mined citations for rs1223430276 ...

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 Aug 16, 2026