22-20992304-C-T

Position:

chr22-20992304-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM3

This summary comes from the ClinGen Evidence Repository: The NM_006767.4:c.1084C>T (p.Arg362Ter) variant in LZTR1 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 10/21 and lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population filtering allele frequency in gnomAD v2.1 is 0.00003426 (15/251042 alleles) in the European (non-Finnish) population. Evidence supports that this variant is associated with AR NS and is not associated with AD NS. This variant has been detected in 1 individual with NS. That individual was compound heterozygous for the variant and another loss of function pathogenic variant confirmed in trans by parental testing (c.1149+1G>T) (PM3, PMID:31182298). Schwannomatosis has been observed in individuals harboring this variant (PMID:29384852). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM3, PVS1. (RASopathy VCEP specifications version 1.1; 9/17/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10118715/MONDO:0021060/094

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 stop_gained

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:17

Conservation

PhyloP100: 1.20

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 10 ACMG points.

PVS1

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

PM3

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.1084C>T	p.Arg362Ter	stop_gained	10/21	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.1084C>T	p.Arg362Ter	stop_gained	10/21		NM_006767.4	ENSP00000496779	P1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000598

AC:

AN:

251042

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000746

AC:

109

AN:

1461696

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000818

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000356

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

LZTR1-related schwannomatosis

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PS4_Supporting+PM3+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 23, 2021	_x000D_ Criteria applied: PVS1, PS4_SUP -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 03, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2024	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Occurred with another LZTR1 variant on the opposite allele (in trans) in a patient with features consistent with a RASopathy in published literature (PMID: 31182298); This variant is associated with the following publications: (PMID: 31980526, 35840934, Santoro2021[abstract], 35251316, 29409008, 34308104, 29384852, 31182298, 38333672, 36113475) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Arg362*) in the LZTR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LZTR1 are known to be pathogenic (PMID: 24362817, 25335493, 25480913, 25795793, 29469822, 30368668, 30442762, 30442766, 30481304, 30859559). This variant is present in population databases (rs189150283, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with schwannomatosis and autosomal recessive Noonan syndrome (PMID: 29384852, 31182298). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 289969). For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 08, 2020	This variant was identified as compound heterozygous with NM_006767.3:c.347C>G. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -

Noonan syndrome 10

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Jul 05, 2023

PVS1, PM2, PM3 -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Sep 15, 2021

ACMG classification criteria: PVS1, PS4, PM2, PM3 -

LZTR1-related schwannomatosis;C4225280:Noonan syndrome 10

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2023

The p.R362* pathogenic mutation (also known as c.1084C>T), located in coding exon 10 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1084. This changes the amino acid from an arginine to a stop codon within coding exon 10. This alteration has been reported in an individual with clinically diagnosed schwannomatosis as well as in a patient with autosomal recessive Noonan syndrome (Jordan JT et al. Medicine (Baltimore), 2018 Feb;97:e9717; Perin F et al. Rev Esp Cardiol (Engl Ed), 2019 Nov;72:978-980). 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

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Nov 25, 2019

Variant summary: LZTR1 c.1084C>T (p.Arg362X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Germline loss of function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014). The variant allele was found at a frequency of 6e-05 in 251042 control chromosomes (gnomAD). As a gene with a pLI score of 0 (gnomAD) this gene is expected to be tolerant to loss of function variants. Therefore, this frequency does not allow any conclusions about variant significance in relation to Schwannomatosis. The variant, c.1084C>T, has been reported in the literature in individuals affected with Schwannomatosis (Jordan_2018, Louvrier_2018) as well as one individual in the 1000 Genome cohort without phenotypic information (Piotrowski_2014) and in a sequencing study of healthy participants (Hou_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Short stature

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Nov 18, 2001

- -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

RASopathy

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Sep 17, 2024

The NM_006767.4:c.1084C>T (p.Arg362Ter) variant in LZTR1 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 10/21 and lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population filtering allele frequency in gnomAD v2.1 is 0.00003426 (15/251042 alleles) in the European (non-Finnish) population. Evidence supports that this variant is associated with AR NS and is not associated with AD NS. This variant has been detected in 1 individual with NS. That individual was compound heterozygous for the variant and another loss of function pathogenic variant confirmed in trans by parental testing (c.1149+1G>T) (PM3, PMID:31182298). Schwannomatosis has been observed in individuals harboring this variant (PMID:29384852). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM3, PVS1. (RASopathy VCEP specifications version 1.1; 9/17/2024). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.82

MutationTaster

Benign

1.0

A;A

Vest4

0.10

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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