rs869320686

Positions:

chr22-20990476-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS2PS4_ModeratePS3_SupportingPP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_006767.4:c.742G>A (p.Gly248Arg) variant in LZTR1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 248. Evidence supports that this variant is associated with AD NS and is not associated with AR NS. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.839, which is above the threshold of 0.7, evidence that correlates with impact to LZTR1 function (PP3). ERK1/2 phosphorylation assays in HEK293 cells showed enhanced EGF-dependent ERK1/2 phosphorylation indicating that this variant impacts protein function (PMID:30481304)(PS3_Supporting). This variant has been reported in 3 probands with features of RASopathy (PS4_Moderate; PMID:25795793, 30859559, 31533111). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:30859559). Schwannomatosis has not been observed in individuals harboring this variant. 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, PS3_Supporting, PM2_Supporting, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA358852/MONDO:0021060/094

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 missense

Scores

12

6

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:23O:1

Conservation

PhyloP100: 9.95

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:

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/exons	MANE	Protein	UniProt
LZTR1	NM_006767.4 linkuse as main transcript	c.742G>A	p.Gly248Arg	missense_variant	8/21	ENST00000646124.2	NP_006758.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2 linkuse as main transcript	c.742G>A	p.Gly248Arg	missense_variant	8/21		NM_006767.4	ENSP00000496779	P1

Frequencies

GnomAD3 genomes

Cov.:

33

GnomAD4 exome

AF:

0.00000411

AC:

6

AN:

1461616

Hom.:

0

Cov.:

32

AF XY:

0.00000413

AC XY:

3

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

33

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Noonan syndrome 10

Pathogenic:9Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 01-22-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Apr 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 26, 2024	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Human Genetics, Universidade de São Paulo	Jun 27, 2022	This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Biologia Molecular - Genetica, Hospital de Pediatria Garrahan	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Dec 27, 2022	PS2, PS3, PM1, PM2, PM5, PP3, PP5 -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 03, 2020	ACMG codes:PS3, PS4M, PM1, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 25, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP1 supporting, PP3 supporting -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 28, 2020	The LZTR1 c.742G>A; p.Gly248Arg variant (rs869320686) is reported in the literature in individuals with Noonan syndrome (Umeki 2018, Jin 2017), is reported to segregate with disease (Yamamoto 2015), and is reported as occurring de novo in some affected individuals (Pagnamenta 2019). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 209088) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 248 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, this variant occurs in the Kelch functional domain and transfected variant protein results in enhanced ERK1/2 photphorylation (Motta 2019). Considering available information, this variant is classified as pathogenic. References: Jin SC et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet. 2017 Nov;49(11):1593-1601. Motta M et al. Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. Hum Mol Genet. 2019 Mar 15;28(6):1007-1022. Pagnamenta AT et al. Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome. Clin Genet. 2019 Jun;95(6):693-703. Umeki I et al. Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. Hum Genet. 2019 Jan;138(1):21-35. Yamamoto GL et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015 Jun;52(6):413-21. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the LZTR1 protein (p.Gly248Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 25795793, 30368668, 30859559). 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: 209088). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2022	Published functional studies demonstrate a damaging effect due to upregulation of the RAS-MAPK signaling pathway (Motta et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26446362, 27942422, 31533111, 23917401, 25795793, 28944487, 30481304, 28991257, 30368668, 31324109, 30859559, 31825158, 32981126, 32368696) -

RASopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2024	Variant summary: LZTR1 c.742G>A (p.Gly248Arg) results in a non-conservative amino acid change located in the Kelch repeat type 1 (IPR006652) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.742G>A has been reported in the literature in multiple individuals (including familial and de novo cases) affected with Noonan Syndrome And Related Conditions (e.g. Clinton_2020, Umeki_2019, Yamamoto_2015). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to result in increased RAS activation and upregulation of the MAPK pathway, consistent with a gain-of-function molecular mechanism of disease (Bigenzahn_2018, Motta_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30442766, 31825158, 30481304, 30859559, 30442762, 30368668, 25795793). ClinVar contains an entry for this variant (Variation ID: 209088). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	The NM_006767.4:c.742G>A (p.Gly248Arg) variant in LZTR1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 248. Evidence supports that this variant is associated with AD NS and is not associated with AR NS. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.839, which is above the threshold of 0.7, evidence that correlates with impact to LZTR1 function (PP3). ERK1/2 phosphorylation assays in HEK293 cells showed enhanced EGF-dependent ERK1/2 phosphorylation indicating that this variant impacts protein function (PMID: 30481304)(PS3_Supporting). This variant has been reported in 3 probands with features of RASopathy (PS4_Moderate; PMID:25795793, 30859559, 31533111). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:30859559). Schwannomatosis has not been observed in individuals harboring this variant. 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, PS3_Supporting, PM2_Supporting, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) -

Schwannomatosis 2;C4225280:Noonan syndrome 10

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Noonan syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Human Genetics

-

c.742G>A has been reported in the literature as being causative of Noonan Syndrome And Related Conditions (e.g. Clinton_2020, Umeki_2019, Yamamoto_2015). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Experimental evidence suggest this variant to upregulate the RAS MAPK pathway. ClinVar contains an entry for this variant (Variation ID: 205685). -

Schwannomatosis 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Sep 02, 2024

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2020

The p.G248R pathogenic mutation (also known as c.742G>A), located in coding exon 8 of the LZTR1 gene, results from a G to A substitution at nucleotide position 742. The glycine at codon 248 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with a clinical diagnosis of autosomal dominant Noonan syndrome, and has been shown to segregate with disease in several families (Güemes M et al. Horm Res Paediatr, 2019 Sep;92:269-275; Chinton J et al. Am J Med Genet A, 2020 02;182:409-414; Yamamoto GL et al. J Med Genet, 2015 Jun;52:413-21). This alteration has also been shown as a recurrent de novo alteration in individuals with autosomal dominant Noonan syndrome (Chinton J et al. Am J Med Genet A, 2020 02;182:409-414). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is pathogenic for autosomal dominant Noonan syndrome; however, the association of this alteration with an increased risk of LZTR1-related schwannomatosis (SWN) is unknown. -

Fetal cystic hygroma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

-

- -

LZTR1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The LZTR1 c.742G>A variant is predicted to result in the amino acid substitution p.Gly248Arg. This variant has been reported in multiple individuals with autosomal dominant Noonan syndrome and has been reported to be de novo and to segregate with disease (Yamamoto et al. 2015. PubMed ID: 25795793; Pagnamenta et al. 2019. PubMed ID: 30859559). Functional studies indicate this variant results in increased activated RAS and an upregulation of the MAPK pathway (Motta et al. 2018. PubMed ID: 30481304). This variant has not been reported in a large population database and has been interpreted as likely pathogenic/pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/209088/). This variant is interpreted as pathogenic for autosomal dominant Noonan syndrome. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.36

D

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

32

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

D;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.47

D

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.19

D

MutationAssessor

Uncertain

2.0

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.85

D

PROVEAN

Pathogenic

-7.3

D;.

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.69

Gain of catalytic residue at G248 (P = 0.0542);Gain of catalytic residue at G248 (P = 0.0542);

MVP

0.66

MPC

1.8

ClinPred

1.0

D

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.77

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.

Other links and lift over

dbSNP: rs869320686; hg19: chr22-21344765; COSMIC: COSV53144758; COSMIC: COSV53144758;