chr22-20982391-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_006767.4(LZTR1):​c.27delG​(p.Gln10ArgfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,558,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β˜…β˜…).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: -3.33
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 53 pathogenic variants in the truncated region.
PP5
Variant 22-20982391-CG-C is Pathogenic according to our data. Variant chr22-20982391-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 143931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-20982391-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LZTR1NM_006767.4 linkc.27delG p.Gln10ArgfsTer15 frameshift_variant Exon 1 of 21 ENST00000646124.2 NP_006758.2 Q8N653A0A384NL67

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LZTR1ENST00000646124.2 linkc.27delG p.Gln10ArgfsTer15 frameshift_variant Exon 1 of 21 NM_006767.4 ENSP00000496779.1 Q8N653

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152160
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000627
AC:
10
AN:
159396
Hom.:
0
AF XY:
0.0000584
AC XY:
5
AN XY:
85688
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000118
Gnomad EAS exome
AF:
0.0000840
Gnomad SAS exome
AF:
0.0000841
Gnomad FIN exome
AF:
0.0000652
Gnomad NFE exome
AF:
0.0000812
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000320
AC:
45
AN:
1406008
Hom.:
0
Cov.:
32
AF XY:
0.0000288
AC XY:
20
AN XY:
694304
show subpopulations
Gnomad4 AFR exome
AF:
0.0000311
Gnomad4 AMR exome
AF:
0.0000273
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000498
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000342
Gnomad4 OTH exome
AF:
0.0000343
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152276
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

LZTR1-related schwannomatosis Pathogenic:3
Feb 01, 2014
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mar 26, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 19, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:3
Jan 26, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln10Argfs*15) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Noonan syndrome or schwannomatosis (PMID: 24362817, 25480913, 29469822). 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: 143931). For these reasons, this variant has been classified as Pathogenic. -

Apr 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 02, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed with a second LZTR1 variant on the opposite allele (in trans) in an individual with autosomal recessive Noonan syndrome (Johnston et al., 2018); Frameshift 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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25480913, 27856782, 24362817, 29469822) -

Noonan syndrome 10 Pathogenic:2
Feb 14, 2023
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The frameshift c.27del(p.Gln10ArgfsTer15) variant in LZTR1 gene has been reported previously in heterozygous state in multiple individuals affected with LZTR1-related disorders (Johnston JJ, et. al., 2018; Smith MJ, et. al., 2015; Piotrowski A, et. al., 2014). The p.Gln10ArgfsTer15 variant has been reported with allele frequency of 0.006% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Glutamine 10, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Gln10ArgfsTer15. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in this gene have been previously reported to be pathogenic (Bigenzahn JW, et. al., 2018; Steklov M, et. al., 2018). For these reasons, this variant has been classified as Pathogenic. -

Sep 23, 2022
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 supporting, PM3 moderated -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Feb 07, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.27delG pathogenic mutation, located in coding exon 1 of the LZTR1 gene, results from a deletion of one nucleotide at nucleotide position 27, causing a translational frameshift with a predicted alternate stop codon (p.Q10Rfs*15). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in multiple individuals with schwannomatosis, as well as in trans with LZTR1 c.1149+1G>A in an individual with autosomal recessive Noonan syndrome (Piotrowski A et al. Nat. Genet., 2014 Feb;46:182-7; Smith MJ et al. Neurology, 2015 Jan;84:141-7; Johnston JJ et al. Genet. Med., 2018 10;20:1175-1185; Louvrier C et al. Neuro-oncology, 2018 06;20:917-929). 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. -

Noonan syndrome 2 Pathogenic:1
-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The frameshift deletion p.Q10Rfs*15 in LZTR1 (NM_006767.4) has been reported previously in association with schwannomatosis as well as with autosomal recessive Noonan syndrome (Piotrowski et al., 2014; Johnston et al., 2018 et al). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been proven to be disease causing.For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome 2;C3810283:LZTR1-related schwannomatosis;C4225280:Noonan syndrome 10 Pathogenic:1
Jun 13, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs587777613; hg19: chr22-21336680; API