chr22-20995490-C-T

Variant names:

• chr22-20995490-C-T
• rs761685529
• ENST00000463909.1:n.402C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3_Supporting PVS1 PM2_Supporting PM3_Strong PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1943-256C>T (p.T648fs*36) variant in LZTR1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17/21 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 0.00001557 (2/22704 alleles) in the South Asian population, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 4 individuals with RASopathy. All were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 3 of those were confirmed in trans by parental testing (c.27dup (p.Gln10Alafs*24), c.1030del (p.Ser344fs), c.2178C>A (p.Tyr726Ter), c.27dupG (p.Gln10Alafs*24), 3.5 PM3 points, PMIDs: 29469822 and 32623905, SCV000748478.4, SCV001445973.1, GeneDx, Broad Center for Mendelian Genomics) (PM3_Strong). The variant has been reported to segregate with RASopathy in ≥7 affected meioses from 4 families (PP1_Strong; PMIDs: 29469822 and 32623905, SCV000748478.4, SCV001445973.1, GeneDx, Broad Center for Mendelian Genomics). ERK activation assay in patient-specific cardiomyocytes showed significantly increased levels of phosphorylated ERK indicating that this variant impacts protein 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_Strong, PP1_Strong, PS3_Supporting, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10119150/MONDO:0021060/094

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: LZTR1 ENST00000463909.1 non_coding_transcript_exon
• Scores: Splicing: ADA: 0.00002255
• Clinical Significance: Pathogenic reviewed by expert panel P:10 U:1
• Conservation: PhyloP100: -0.680
• Publications: 6 publications found

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

ENSG00000285314 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 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.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LZTR1	NM_006767.4	c.1943-256C>T		intron_variant	Intron 16 of 20	ENST00000646124.2	NP_006758.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2	c.1943-256C>T		intron_variant	Intron 16 of 20		NM_006767.4	ENSP00000496779.1

Frequencies

GnomAD3 genomes AF: 0.0000791 AC: 12 AN: 151688 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000407 AC: 6 AN: 147296 AF XY: 0.0000376

Gnomad AFR exome AF: 0.000141

Gnomad AMR exome AF: 0.0000416

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000793 AC: 41 AN: 517156 Hom.: 0 Cov.: 4 AF XY: 0.0000822 AC XY: 23 AN XY: 279928

African (AFR) AF: 0.0000683 AC: 1 AN: 14652

American (AMR) AF: 0.0000309 AC: 1 AN: 32360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18304

East Asian (EAS) AF: 0.0000357 AC: 1 AN: 28036

South Asian (SAS) AF: 0.0000810 AC: 5 AN: 61698

European-Finnish (FIN) AF: 0.0000696 AC: 3 AN: 43078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3756

European-Non Finnish (NFE) AF: 0.000101 AC: 29 AN: 287496

Other (OTH) AF: 0.0000360 AC: 1 AN: 27776

GnomAD4 genome AF: 0.0000791 AC: 12 AN: 151688 Hom.: 0 Cov.: 32 AF XY: 0.0000810 AC XY: 6 AN XY: 74078

African (AFR) AF: 0.000170 AC: 7 AN: 41250

American (AMR) AF: 0.00 AC: 0 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.0000949 AC: 1 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67936

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000907

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 2 Pathogenic:3 Uncertain:1

Nov 11, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LZTR1 c.1943-256C>T is located within intron 16 at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic 5' donor site. At least two publications report experimental evidence that this variant indeed affects mRNA splicing, resulting in the inclusion of the additional 117 bp cryptic exon between exons 16 and 17 (e.g. Johnston_2018, Hanses_2020). The variant allele was found at a frequency of 4.1e-05 in 147296 control chromosomes (gnomAD). c.1943-256C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Noonan Syndrome 2 from at least five different families in which the variant was found to segregate with the disease in an autosomal recessive pattern of inheritance (e.g. Johnston_2018, Hanses_2020). These data indicate that the variant is very likely to be associated with disease. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as pathogenic (n=3) and one classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 01, 2017

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This family has been reported in PMID:29469822. -

Dec 17, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous c.1943-256C>T variant in LZTR1 was identified by our study in the compound heterozygous state, along with another likely pathogenic variant, in 2 siblings with Noonan syndrome 2. The variant has been reported in 8 individuals of unknown ethnicity with Noonan syndrome 2 (PMID: 29469822, 32623905) and segregated with disease in 4 affected relatives from 3 families (PMID: 29469822, 32623905). This variant has been identified in 0.019% (3/15796) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs761685529). Although the c.1943-256C>T variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 522800) as pathogenic by OMIM and GeneDx, and as having unknown significance by the Undiagnosed Diseases Network, NIH. Of the 10 affected individuals, 2 of those were homozygotes, 5 were compound heterozygotes that carried a reported pathogenic/likely pathogenic variants in trans, and 3 were compound heterozygotes that carried a variants of uncertain significance in trans, which increases the likelihood that the c.1943-256C>T variant is pathogenic (VariationID: 522799, 372684; PMID: 29469822, 32623905). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 29469822, 32623905). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Noonan syndrome 2. ACMG/AMP Criteria applied: PM3_strong, PP1_strong, PS3_moderate (Richards 2015). -

not provided Pathogenic:2

Feb 11, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in loss-of-function; inclusion of 117bp from an alternate exon lead to a truncated protein, p.(T648fs*36), that was subject to nonsense mediated decay (Johnston et al., 2018; Hanses et al. 2020); This variant is associated with the following publications: (PMID: 29469822, 32623905, 34747535) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 16 of the LZTR1 gene. It does not directly change the encoded amino acid sequence of the LZTR1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs761685529, gnomAD 0.02%). This variant has been observed in individuals with Noonan syndrome (PMID: 29469822, 32623905). ClinVar contains an entry for this variant (Variation ID: 522800). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 29469822, 32623905). For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome Pathogenic:2

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a homozygous and compound heterozygous change in individuals with Noonan syndrome and shown to moderately segregate with disease in two families (PMID: 29469822). Heterozygous carrier parents demonstrated mild or no clinical manifestations (PMID: 29469822). Splicing studies using the RNA from a patient's lymphoblasts showed an abnormal product retaining a 117bp sequence from intron 16 (PMID: 29469822). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (11/178598) and is absent in the homozygous state, and thus is presumed to be rare. Based on the available evidence, the c.1943-256C>T variant is classified as Pathogenic. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LZTR1-related schwannomatosis Pathogenic:1

Dec 21, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1

Dec 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1943-256C>T intronic pathogenic mutation results from a C to T substitution 256 nucleotides upstream from coding exon 17 in the LZTR1 gene. This alteration has been reported in multiple individuals diagnosed with autosomal recessive Noonan syndrome in trans with other mutations or in the homozygous state and was shown to segregate with disease in several families (Johnston JJ et al. Genet Med. 2018 Oct;20(10):1175-1185). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. RNA studies demonstrated that this alteration results in the retention of a 117-base pair alternate exon that lies within intron 16 (Johnston JJ et al. Genet Med. 2018 Oct;20(10):1175-1185; Hanses U et al. Circulation, 2020 Sep;142:1059-1076; Ambry internal data). 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. -

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.1943-256C>T (p.T648fs*36) variant in LZTR1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17/21 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 0.00001557 (2/22704 alleles) in the South Asian population, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 4 individuals with RASopathy. All were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 3 of those were confirmed in trans by parental testing (c.27dup (p.Gln10Alafs*24), c.1030del (p.Ser344fs), c.2178C>A (p.Tyr726Ter), c.27dupG (p.Gln10Alafs*24), 3.5 PM3 points, PMIDs: 29469822 and 32623905, SCV000748478.4, SCV001445973.1, GeneDx, Broad Center for Mendelian Genomics) (PM3_Strong). The variant has been reported to segregate with RASopathy in ≥7 affected meioses from 4 families (PP1_Strong; PMIDs: 29469822 and 32623905, SCV000748478.4, SCV001445973.1, GeneDx, Broad Center for Mendelian Genomics). ERK activation assay in patient-specific cardiomyocytes showed significantly increased levels of phosphorylated ERK indicating that this variant impacts protein 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_Strong, PP1_Strong, PS3_Supporting, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	15
DANN	Benign	0.65
PhyloP100		-0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs761685529; hg19: chr22-21349779;