rs761685529

Variant names:

• chr22-20995490-C-T
• rs761685529
• NM_006767.4:c.1943-256C>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 NM_006767.4 intron
• Scores: Splicing: ADA: 0.00002255
• Clinical Significance: Pathogenic reviewed by expert panel P:11 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Noonan syndrome 10

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• schwannomatosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Noonan syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• Costello syndrome

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• cardiofaciocutaneous syndrome

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	NM_006767.4	MANE Select	c.1943-256C>T		intron	N/A	NP_006758.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	ENST00000646124.2	MANE Select	c.1943-256C>T		intron	N/A	ENSP00000496779.1	Q8N653
	LZTR1	ENST00000463909.1	TSL:1	n.402C>T		non_coding_transcript_exon	Exon 1 of 4
	LZTR1	ENST00000888029.1		c.1940-256C>T		intron	N/A	ENSP00000558088.1

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

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	1	-	Noonan syndrome 2 (4)
3	-	-	not provided (3)
2	-	-	Noonan syndrome (2)
1	-	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
1	-	-	LZTR1-related schwannomatosis (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

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;