22-20991686-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PS3_ModeratePM2_SupportingPS4_SupportingPS2

This summary comes from the ClinGen Evidence Repository: The NM_006767.4:c.850C>T variant in LZTR1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 284 (p.Arg284Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.801, which is above the threshold of 0.7, evidence that correlates with impact to LZTR1 function (PP3). This variant has been reported in 1 proband meeting NS diagnostic criteria (PS4_Supporting; PMID:25795793). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with Noonan syndrome (PS2; PMID:25795793). RAS, MEK, and ERK activation in HEK293T cells showed increased level of endogenous active, GTP-bound RAS and increased phosphorylation of MEK and ERK, indicating that this variant impacts protein function (PMID:30481304)(PS3_Moderate). 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, PS3_Moderate, PS4_Supporting, PM2_Supporting, PP3. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA204980/MONDO:0021060/094

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 2.98

Variant links:

Genes affected

LZTR1 (HGNC:6742): (leucine zipper like post translational regulator 1) This gene encodes a member of the BTB-kelch superfamily. Initially described as a putative transcriptional regulator based on weak homology to members of the basic leucine zipper-like family, the encoded protein subsequently has been shown to localize exclusively to the Golgi network where it may help stabilize the Gogli complex. Deletion of this gene may be associated with DiGeorge syndrome. [provided by RefSeq, Jul 2008]

LZTR1 links:

ENSG00000285314 (HGNC:):

ENSG00000285314 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS2

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LZTR1	NM_006767.4 link	c.850C>T	p.Arg284Cys	missense_variant	Exon 9 of 21	ENST00000646124.2	NP_006758.2	Q8N653A0A384NL67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2 link	c.850C>T	p.Arg284Cys	missense_variant	Exon 9 of 21		NM_006767.4	ENSP00000496779.1		Q8N653

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000689

AC:

AN:

1451524

Hom.:

Cov.:

AF XY:

0.00000832

AC XY:

AN XY:

721506

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000902

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Noonan syndrome 10

Pathogenic:4

Sep 06, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2019

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.850C>Tp.Arg284Cys variant in LZTR1 gene has been reported previously in multiple individuals affected with autosomal dominant LZTR1-related disorders / Noonan syndrome Jacquinet A, et al., 2020; Yamamoto GL, et al., 2015; Paganini I, et al., 2015. This variant has also been observed to segregate with disease in related individuals. Experimental evidence demonstrates that this variant results in the upregulation of RAS-MAPK signaling and affects LZTR1 function Motta M, et al., 2019. The p.Arg284Cys variant is present with allele frequency of 0.0% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. Multiple lines of computational evidences Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on LZTR1 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 284 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:3

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LZTR1: PS2, PM2, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting -

Nov 12, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). 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 have shown that this missense change affects LZTR1 function (PMID: 30481304). For these reasons, this variant has been classified as Pathogenic. -

LZTR1-related schwannomatosis;C4225280:Noonan syndrome 10

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Nov 01, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Noonan syndrome 2;C3810283:LZTR1-related schwannomatosis;C4225280:Noonan syndrome 10

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3+PS4_Moderate+PP1_Moderate+PS2_Moderate -

LZTR1-related disorder

Pathogenic:1

Jul 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;D

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.8

H;H

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.3

D;.

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.92

Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);

MVP

0.82

MPC

2.0

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over