22-20995865-C-T

Position:

chr22-20995865-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5

The NM_006767.4(LZTR1):c.2062C>T(p.Arg688Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,612,788 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 5.03

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 5 ACMG points.

PM1

In a domain BTB 2 (size 69) in uniprot entity LZTR1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006767.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

PP5

Variant 22-20995865-C-T is Pathogenic according to our data. Variant chr22-20995865-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 101036.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LZTR1	NM_006767.4 linkuse as main transcript	c.2062C>T	p.Arg688Cys	missense_variant	17/21	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.2062C>T	p.Arg688Cys	missense_variant	17/21		NM_006767.4	ENSP00000496779	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000443

AC:

AN:

248230

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135008

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000537

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1460692

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726674

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000333

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Schwannomatosis 2

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	May 17, 2021	The p.Arg688Cys variant in the LZTR1 gene has been previously reported in 4 unrelated individuals with schwannomatosis who were heterozygous for this variant (Piotrowski et al., 2014; Smith et al., 2015; Steklov et al., 2018). This variant has also been reported in 1 individual with Noonan Syndrome, who was compound heterozygous for this variant (Pagnamenta et al., 2019). The p.Arg688Cys variant was determined to be in trans with a likely pathogenic variant (c.1149+1G>T), consistent with autosomal recessive inheritance (Pagnamenta et al., 2019). The presence of this variant with a likely disease-causing variant on the opposite allele increases suspicion for its pathogenicity. The p.Arg688Cys variant has also been identified in 3/24,262 African/African-Amerian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Additionally, two different amino acid changes, p.Arg688His and p.Arg688Gly, have been previously reported at this residue, although the evidence for these variants is insufficient to classify them as disease-causing. The p.Arg688His variant was reported as heterozygous in a patient with schwannomatosis (Steklov et al., 2018). The p.Arg688Gly variant was reported in trans with a disease-causing variant (c.1943-256C>T) in an individual with Noonan Syndrome (Johnston et al., 2018). Functional studies of this variant have been reported; however, it is currently unclear if this would be sufficientto be disease-causing (Steklov et al., 2018). Computational tools predict that the p.Arg688Cys variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of thep.Arg688Cysvariant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PM3; PP3] -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2023	Reported as de novo in a patient with unexplained developmental delay (DD) or intellectual disability (ID), but this patient also harbored a de novo pathogenic variant in the TCF4 gene which could explain the phenotype (Hiraide et al., 2021); Published functional studies suggests this variant may have an affect on cellular localization of the LZTR1 protein (Steklov et al., 2018); 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: 35840934, 29469822, 33792302, 34913528, 25480913, 33407364, 30442762, 24362817, 33644862, 30859559) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 688 of the LZTR1 protein (p.Arg688Cys). This variant is present in population databases (rs587777178, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal dominant schwannomatosis and/or autosomal recessive Noonan syndrome (PMID: 24362817, 25480913, 30859559). 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: 101036). 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. Experimental studies have shown that this missense change affects LZTR1 function (PMID: 30442762). This variant disrupts the p.Arg688 amino acid residue in LZTR1. Other variant(s) that disrupt this residue have been observed in individuals with LZTR1-related conditions (PMID: 29469822, 30859559), which suggests that this may be a clinically significant amino acid residue. 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. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2023

The p.R688C variant (also known as c.2062C>T), located in coding exon 17 of the LZTR1 gene, results from a C to T substitution at nucleotide position 2062. The arginine at codon 688 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in conjunction with LZTR1 c.1149-1G>T (phase unknown) in a patient with a presumed Noonan syndrome diagnosis (Pagnamenta AT et al. Clin. Genet., 2019 Jun;95:693-703). This variant has also been reported in multiple individuals with schwannomatosis (Piotrowski A et al. Nat. Genet., 2014 Feb;46:182-7; Smith MJ et al. Neurology, 2015 Jan;84:141-7; Steklov M et al. Science, 2018 12;362:1177-1182). A functional study suggests that this alteration may impair complex formation with CUL3 and affect subcellular localization (Steklov M et al. Science, 2018 12;362:1177-1182). This amino acid position is well 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. -

LZTR1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2023

The LZTR1 c.2062C>T variant is predicted to result in the amino acid substitution p.Arg688Cys. This variant was reported individuals with autosomal dominant schwannomatosis (Piotrowski et al. 2014. PubMed ID: 24362817; Smith et al. 2015. PubMed ID: 25480913, Steklov et al. 2018. PubMed ID: 30442762) and in a patient with autosomal recessive Noonan syndrome (Patient 279914 in Pagnamenta et al. 2019. PubMed ID: 30859559). It was also reported to be de novo in a patient from a cohort of individuals with developmental delay/intellectual disability; however, this patient also had a de novo pathogenic variant in TCF4 (Hiraide et al. 2021. PubMed ID: 33644862). However, one of the cases reported in Piotrowski et al. found that the variant was inherited from an asymptomatic father (Piotrowski et al. 2014. PubMed ID: 24362817). Functional analysis showed that the variant lead to reduced CUL3 binding (Steklov et al. 2018. PubMed ID: 30442762). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21350154-C-T). This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely pathogenic to uncertain (https://ncbi.nlm.nih.gov/clinvar/variation/). Of note, different variants at the same amino acid (p.Arg688Gly and p.Arg688His) have also been reported in a patient with autosomal recessive Noonan syndrome (Johnston et al. 2018. PubMed ID: 29469822) and in patients with schwannomatosis (Steklov et al. 2018. PubMed ID: 30442762). Based on this evidence, we interpret the c.2062C>T (p.Arg688Cys) variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;D

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

.;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.3

D;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;D

Vest4

0.92

MVP

0.53

MPC

0.40

ClinPred

0.84

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.76

gMVP

0.92

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