22-20982391-CGGGGG-CGGGGGG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3_SupportingPVS1PM3

This summary comes from the ClinGen Evidence Repository: The c.27dup (p.Gln10fs) variant in LZTR1 is a frameshift variant predicted to cause a premature stop codon 24 amino acids downstream in biologically-relevant-exon 1 (of 21) and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001139 (4/13466 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in 1 individual with RASopathy. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and which was confirmed in trans by family testing (c.1943-256C>T (p.T648fs*36), 1 PM3 point, PMID:32623905) (PM3). ERK activation assay in patient-specific cardiomyocytes showed significantly increased levels of phosphorylated ERK supporting the abnormal impact due to loss of LZTR1 function (PMID:32623905)(PS3_Supporting). 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: PVS1, PM3, PS3_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10118264/MONDO:0021060/094

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:7O:1

Conservation

PhyloP100: -3.33

Publications

10 publications found

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 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

LZTR1 links:

ENSG00000285314 (HGNC:):

ENSG00000285314 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

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

PS3

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

PM3

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006767.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	NM_006767.4	MANE Select	c.27dupG	p.Gln10AlafsTer24	frameshift	Exon 1 of 21	NP_006758.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LZTR1	ENST00000646124.2	MANE Select	c.27dupG	p.Gln10AlafsTer24	frameshift	Exon 1 of 21	ENSP00000496779.1
LZTR1	ENST00000700578.1		c.27dupG	p.Gln10AlafsTer24	frameshift	Exon 1 of 20	ENSP00000515073.1
LZTR1	ENST00000645935.1		c.27dupG	p.Gln10AlafsTer24	frameshift	Exon 1 of 4	ENSP00000493479.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000100

AC:

AN:

159396

AF XY:

0.0000817

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000336

Gnomad FIN exome

AF:

0.0000652

Gnomad NFE exome

AF:

0.0000975

Gnomad OTH exome

AF:

0.000226

GnomAD4 exome

AF:

0.0000669

AC:

AN:

1405972

Hom.:

Cov.:

AF XY:

0.0000792

AC XY:

AN XY:

694278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32178

American (AMR)

AF:

0.0000273

AC:

AN:

36580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25208

East Asian (EAS)

AF:

0.000191

AC:

AN:

36642

South Asian (SAS)

AF:

0.000112

AC:

AN:

80266

European-Finnish (FIN)

AF:

0.000310

AC:

AN:

48358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.0000545

AC:

AN:

1082802

Other (OTH)

AF:

0.0000515

AC:

AN:

58248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000261

Hom.:

Bravo

AF:

0.0000793

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jan 30, 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.Gln10Alafs*24) 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 autosomal recessive Noonan syndrome (PMID: 32623905). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372684). For these reasons, this variant has been classified as Pathogenic.

Aug 19, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 33897756, 24077912, 32623905, 30368668, 35861108, 38496821)

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LZTR1: PVS1, PM2

LZTR1-related schwannomatosis

Pathogenic:1

Mar 04, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Nov 07, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.27dupG pathogenic mutation, located in coding exon 1 of the LZTR1 gene, results from a duplication of G at nucleotide position 27, causing a translational frameshift with a predicted alternate stop codon (p.Q10Afs*24). This alteration has been reported in two siblings with autosomal recessive Noonan syndrome (Hanses U et al. Circulation, 2020 09;142:1059-1076). 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

Jun 01, 2022

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.27dupG (p.Gln10AlafsX24) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.0001 in 159396 control chromosomes. This frequency does not allow conclusions about variant significance. c.27dupG has been reported in the literature in individuals affected with autosomal recessive Noonan Syndrome (example, Hanses_2020, Zhou_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Germline loss of function mutations in LZTR1 have also been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014). Based on the evidence outlined above, the variant was classified as likely pathogenic for the risk of multiple schwannomas and Autosomal Recessive Noonan syndrome.

RASopathy

Pathogenic:1

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.27dup (p.Gln10fs) variant in LZTR1 is a frameshift variant predicted to cause a premature stop codon 24 amino acids downstream in biologically-relevant-exon 1 (of 21) and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001139 (4/13466 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in 1 individual with RASopathy. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and which was confirmed in trans by family testing (c.1943-256C>T (p.T648fs*36), 1 PM3 point, PMID: 32623905) (PM3). ERK activation assay in patient-specific cardiomyocytes showed significantly increased levels of phosphorylated ERK supporting the abnormal impact due to loss of LZTR1 function (PMID:32623905)(PS3_Supporting). 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: PVS1, PM3, PS3_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024)

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-3.3

Mutation Taster

=16/184

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over