rs587777180

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong

The NM_006767.4(LZTR1):c.1397G>A(p.Arg466Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.76

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 Pathogenic. Variant got 12 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-20993966-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

PP5

Variant 22-20993967-G-A is Pathogenic according to our data. Variant chr22-20993967-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 101038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LZTR1	NM_006767.4 linkuse as main transcript	c.1397G>A	p.Arg466Gln	missense_variant	13/21	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.1397G>A	p.Arg466Gln	missense_variant	13/21		NM_006767.4	ENSP00000496779	P1

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000323

AC:

AN:

247306

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

134152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000989

Gnomad FIN exome

AF:

0.0000956

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1460350

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726432

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000697

Gnomad4 FIN exome

AF:

0.0000381

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000645

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 29, 2022	The LZTR1 c.1397G>A; p.Arg466Gln variant (rs587777180) is reported in the literature in multiple heterozygous individuals affected with schwannomatosis (Piotrowski 2014, Steklov 2018), as well as an individual with Noonan syndrome that carried a second missense variant in trans (Li 2019). The p.Arg466Gln variant is found in the general population with an overall allele frequency of 0.003% (8/247,306 alleles) in the Genome Aggregation Database. The arginine at codon 466 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.918). Consistent with predictions, functional studies suggest the variant protein has altered cellular localization, reduced interaction with the binding partner protein CUL3, and is associated with elevated levels of Ras signaling (Bigenzahn 2018, Steklov 2018). Based on available information, this variant is considered to be likely pathogenic in association with schwannoma susceptibility and autosomal recessive Noonan syndrome. References: Bigenzahn JW et al. LZTR1 is a regulator of RAS ubiquitination and signaling. Science. 2018 Dec 7;362(6419):1171-1177. PMID: 30442766. Li X et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 2019 Oct;96(4):290-299. PMID: 31219622. Piotrowski A et al. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet. 2014 Feb;46(2):182-7. PMID: 24362817. Steklov M et al. Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. Science. 2018 Dec 7;362(6419):1177-1182. PMID: 30442762. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 12, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 466 of the LZTR1 protein (p.Arg466Gln). This variant is present in population databases (rs587777180, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of schwannomatosis and Noonan syndrome (PMID: 24362817, 30442762, 31130284, 31219622; Invitae). ClinVar contains an entry for this variant (Variation ID: 101038). 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: 30442762). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Schwannomatosis 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 23, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2023

The p.R466Q variant (also known as c.1397G>A), located in coding exon 13 of the LZTR1 gene, results from a G to A substitution at nucleotide position 1397. The arginine at codon 466 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with schwannomatosis (Piotrowski A et al. Nat Genet, 2014 Feb;46:182-7; Steklov M et al. Science, 2018 12;362:1177-1182; Ambry internal data). The alteration was also identified in an individual with Noonan syndrome who had another LZTR1 alteration in trans (Li X et al. Clin Genet, 2019 10;96:290-299). One functional study suggested that this alteration may impair complex formation with CUL3 and cellular localization (Steklov M et al. Science, 2018 12;362:1177-1182). 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 variant is likely pathogenic for an increased risk of LZTR1-related schwannomatosis (SWN) and would be expected to cause autosomal recessive Noonan syndrome when present along with a second pathogenic variant on the other allele. -

Schwannomatosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 16, 2020

Variant summary: LZTR1 c.1397G>A (p.Arg466Gln) results in a conservative amino acid change located in the BTB/POZ domain (IPR000210) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 247306 control chromosomes (gnomAD). c.1397G>A has been reported in the literature in at least three individuals affected with Schwannomatosis (Piotrowski_2014, Steklov_2018). These data indicate that the variant may be associated with disease. The variant has also been reported in compound heterozygosity with another missense variant in LZTR1 (c.2455G>C (p.Asp819His)) in a patient affected with Noonan Syndrome, where the patient's mother also carried the variant of interest, but was unaffected (Li_2019). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions (NSRD). Publications also reported experimental evidence, and demonstrated that the variant increased Ras signaling, and resulted in impaired subcellular location (Steklov_2018, Bigenzahn_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic for the risk of multiple schwannomas, and as a variant of uncertain clinical significance for the NSRD phenotype. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 31, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.010

D;.

Polyphen

1.0

D;D

Vest4

0.94

MVP

0.74

MPC

0.37

ClinPred

0.89

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.51

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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