rs587777613

Positions:

• chr22-20982391-CG-C
• chr22-20982391-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_006767.4(LZTR1):​c.27del​(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: LZTR1 NM_006767.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: -3.33

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]

ACMG classification

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/exons	MANE	Protein	UniProt
LZTR1	NM_006767.4	c.27del	p.Gln10ArgfsTer15	frameshift_variant	1/21	ENST00000646124.2	NP_006758.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2	c.27del	p.Gln10ArgfsTer15	frameshift_variant	1/21		NM_006767.4	ENSP00000496779	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152160 Hom.: 0 Cov.: 33

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

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

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

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LZTR1-related schwannomatosis Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2023	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

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 23, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 supporting, PM3 moderated -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

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. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs587777613; hg19: chr22-21336680;