rs587777180

Variant names:

• chr22-20993967-G-A
• rs587777180
• NM_006767.4:c.1397G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-20993967-G-A
• chr22-20993967-G-C
• chr22-20993967-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_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. R466L) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.76
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• LZTR1-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Noonan syndrome 10

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• schwannomatosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Noonan syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ENSG00000285314 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 53 uncertain in NM_006767.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-20993967-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1312561.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 101038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LZTR1	NM_006767.4	c.1397G>A	p.Arg466Gln	missense_variant	Exon 13 of 21	ENST00000646124.2	NP_006758.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2	c.1397G>A	p.Arg466Gln	missense_variant	Exon 13 of 21		NM_006767.4	ENSP00000496779.1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152240 Hom.: 0 Cov.: 34

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

GnomAD2 exomes AF: 0.0000323 AC: 8 AN: 247306 AF XY: 0.0000298

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 FIN exome AF: 0.0000956

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000288 AC: 42 AN: 1460350 Hom.: 0 Cov.: 34 AF XY: 0.0000330 AC XY: 24 AN XY: 726432

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26062

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86042

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111840

Other (OTH) AF: 0.0000663 AC: 4 AN: 60344

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152240 Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6 AN XY: 74384

African (AFR) AF: 0.0000723 AC: 3 AN: 41472

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000904 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Dec 29, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LZTR1: PM5, PS4:Moderate, PM2:Supporting, PS3:Supporting -

Jan 26, 2025

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 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, 36947458; internal data). ClinVar contains an entry for this variant (Variation ID: 101038). 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: 30442762). For these reasons, this variant has been classified as Pathogenic. -

Feb 12, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LZTR1-related schwannomatosis Pathogenic:2

Feb 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 23, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1

May 12, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R466Q pathogenic mutation (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 was reported in individual(s) with features consistent with LZTR1-related schwannomatosis (Piotrowski A et al. Nat Genet, 2014 Feb;46:182-7; Steklov M et al. Science, 2018 Dec;362:1177-1182; Ambry internal data). The variant was also identified in an individual with Noonan syndrome who had another LZTR1 variant in trans (Li X et al. Clin Genet, 2019 Oct;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. Loss-of-function variants in LZTR1 are related to an increased risk for schwannomas and autosomal recessive Noonan syndrome; however, such associations with autosomal dominant Noonan syndrome have not been observed (Piotrowski A et al. Nat Genet. 2014 Feb;46:182-7; Yamamoto GL et al. J Med Genet. 2015 Jun;52:413-21; Johnston JJ et al. Genet Med. 2018 10;20:1175-1185). Based on the supporting evidence, this variant is 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 or likely pathogenic variant on the other allele; however, the association of this alteration with autosomal dominant Noonan syndrome is unlikely. -

Schwannomatosis Pathogenic:1

Sep 16, 2020

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 2 Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.1397G>Ap.Arg466Gln variant in LZTR1 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Noonan syndrome Steklov et al., 2018. This variant is reported with the allele frequency of 0.003% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic. The amino acid Arg at position 466 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg466Gln in LZTR1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence Polyphen - Damaging, SIFT - Damaging, and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Noonan syndrome 2;C3810283:LZTR1-related schwannomatosis;C4225280:Noonan syndrome 10 Pathogenic:1

Mar 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Mar 31, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		7.8
PrimateAI	Uncertain	0.58	T
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	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.87
Mutation Taster		=25/75	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777180; hg19: chr22-21348256; COSMIC: COSV53145166; COSMIC: COSV53145166;