22-20987548-C-T

Position:

chr22-20987548-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_006767.4(LZTR1):c.365C>T(p.Ser122Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4

Conservation

PhyloP100: 7.47

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 Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

PP5

Variant 22-20987548-C-T is Pathogenic according to our data. Variant chr22-20987548-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 101035.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LZTR1	NM_006767.4 linkuse as main transcript	c.365C>T	p.Ser122Leu	missense_variant	4/21	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.365C>T	p.Ser122Leu	missense_variant	4/21		NM_006767.4	ENSP00000496779	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251186

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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

Alfa

AF:

0.0000749

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2024	Published functional studies demonstrate a damaging effect: increased MAPK pathway phosphorylation, decreased binding to RAS, impaired intracellular co-localization of NRAS and LZTR1 (PMID: 30442766, 30442762); Not observed at significant frequency in large population cohorts (gnomAD); 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: 30442762, 30442766, 24362817, 35840934, 32371905, 34113392) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 122 of the LZTR1 protein (p.Ser122Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with schwannomatosis (PMID: 24362817, 30442762). ClinVar contains an entry for this variant (Variation ID: 101035). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	LZTR1: PM2, PP3, PS3:Supporting, PS4:Supporting -

Noonan syndrome 10

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 25, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Loss of function variants result in a recessive form of Noonan syndrome and schwannomatosis. Gain of function missense cause a dominant Noonan syndrome (OMIM, PMID: 25795793, PMID: 30481304. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. While schwannomatosis is regarded autosomal dominant, a second somatic mutation is required to establish disease (OMIM). (N) 0112 - Variants in this gene causing schwannomatosis are known to have reduced penetrance (PMID:24362817). (N) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine (exon 4). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygote). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (motif I within the Kelch domain; PMID: 24362817). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in 1 family with schwannomatosis (ClinVar, PMID: 24362817). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence where transfected cells demonstrated reduced protein binding and failure to prevent MAPK pathway activation (PMID:30442762; PMID:30442766). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

LZTR1-related schwannomatosis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2014

- -

LZTR1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2024

The LZTR1 c.365C>T variant is predicted to result in the amino acid substitution p.Ser122Leu. This variant has been documented in multiple individuals with schwannomas (Piotrowski et al. 2014. PubMed ID: 24362817; Steklov et al. 2018. PubMed ID: 30442762) or an unspecified central nervous system tumor (Patient SJCNS042493 in Table S6 - Akhavanfard et al. 2020. PubMed ID: 32371905). In one individual tumor sequencing of the schwannoma found a somatic deletion of 22q11.2 (involving the LZTR1 and NF2 genes) and another somatic variant affecting NF2 consistent with LZTR1-related schwannomatosis (Supplemental Figure 1- Piotrowski et al. 2014. PubMed ID: 24362817). This variant falls within the Kelch domain which is responsible for substrate binding. Co-IP assays of this variant along with other missense variants within the Kelch domain showed decreased RAS binding and co-localization indicating this variant results in a loss-of-function (Steklov et al. 2018. PubMed ID: 30442762). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations in ClinVar of uncertain and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/101035/). This variant is interpreted as likely pathogenic in the context of autosomal recessive Noonan syndrome and autosomal dominant schwannomatosis with reduced penetrance. However, in the context of autosomal dominant Noonan syndrome the clinical significance of this variant is uncertain. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The p.S122L variant (also known as c.365C>T), located in coding exon 4 of the LZTR1 gene, results from a C to T substitution at nucleotide position 365. The serine at codon 122 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in a patient clinically affected with schwannomatosis and their affected father (Piotrowski A et al. Nat Genet, 2014 Feb;46:182-7). Functional analysis demonstrated that this variant shows decreased binding to panRAS and reduced co-localization with NRAS; however, there is no direct evidence that this alteration affects RAS ubiquination and thus, RAS activation (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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Schwannomatosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Jul 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

T;T;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

.;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.6

H;H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.6

D;.;.

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0070

D;.;.

Sift4G

Uncertain

0.0020

D;.;.

Polyphen

1.0

D;D;.

Vest4

0.97

MutPred

0.64

Loss of disorder (P = 0.0236);Loss of disorder (P = 0.0236);.;

MVP

0.53

MPC

1.6

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.79

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