Variant 22-20982391-CG-CGG details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_006767.4(LZTR1):c.27dup(p.Gln10AlafsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000648 in 1,558,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T7T) has been classified as Likely benign.

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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

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]

LZTR1 links:

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 317 pathogenic variants in the truncated region.

PP5

Variant 22-20982391-C-CG is Pathogenic according to our data. Variant chr22-20982391-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LZTR1	NM_006767.4 linkuse as main transcript	c.27dup	p.Gln10AlafsTer24	frameshift_variant	1/21	ENST00000646124.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LZTR1	ENST00000646124.2 linkuse as main transcript	c.27dup	p.Gln10AlafsTer24	frameshift_variant	1/21		NM_006767.4	P1

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

GnomAD3 exomes

AF:

0.000100

AC:

AN:

159396

Hom.:

AF XY:

0.0000817

AC XY:

AN XY:

85688

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 SAS exome

AF:

0.000168

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000273

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000191

Gnomad4 SAS exome

AF:

0.000112

Gnomad4 FIN exome

AF:

0.000310

Gnomad4 NFE exome

AF:

0.0000545

Gnomad4 OTH exome

AF:

0.0000515

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000793

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2023	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, 32623905, 24077912, 30368668) -

Schwannomatosis 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 04, 2024

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2021

The c.27dupG variant, 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). The predicted stop codon occurs within the first 150 nucleotides of theLZTR1 gene. This alteration may escape nonsense-mediated mRNAdecay and/or be rescued by re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat. Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). However, the impacted region is predicted to disrupt the Kelch domain implicated in interactions (Steklov M et al. Science 2018 12;362:1177-1182; Motta M et al. Hum. Mol. Genet. 2019 03;28:1007-1022). This alteration has been reported in two siblings with autosomal recessive Noonan syndrome (Hanses U et al. Circulation, 2020 09;142:1059-1076). In addition, another alteration resulting in a similar consequence, c.27delG (p.Q10Rfs*15), has been reported in multiple individuals with schwannomatosis, as well as 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Noonan syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 01, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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