rs587777176

Variant names:

• chr22-20985828-G-A
• rs587777176
• NM_006767.4:c.264-13G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_006767.4(LZTR1):​c.264-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: LZTR1 NM_006767.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 U:1
• Conservation: PhyloP100: 0.0700

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]

ENSG00000285314 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 22-20985828-G-A is Pathogenic according to our data. Variant chr22-20985828-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 101034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-20985828-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LZTR1	NM_006767.4	c.264-13G>A		intron_variant	Intron 2 of 20	ENST00000646124.2	NP_006758.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2	c.264-13G>A		intron_variant	Intron 2 of 20		NM_006767.4	ENSP00000496779.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251194 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135866

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727148

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LZTR1-related schwannomatosis Pathogenic:4

Feb 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 23, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Very Strong -

Sep 01, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

Feb 27, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in loss of function (PMID: 24362817); Identified in patients with schwannomatosis in published literature and referred for genetic testing at GeneDx (PMID: 24362817, 31128261, 29409008); This variant is associated with the following publications: (PMID: 24362817, 31128261, 29409008, 31438995, 34426522, 27921248, 36495689) -

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LZTR1: PS3:Moderate, PS4:Moderate, PM2:Supporting, PP1, PP3 -

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 2 of the LZTR1 gene. It does not directly change the encoded amino acid sequence of the LZTR1 protein. This variant is present in population databases (rs587777176, gnomAD 0.02%). This variant has been observed in individuals with schwannomatosis (PMID: 24362817, 31128261, 31438995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 101034). Studies have shown that this variant is associated with altered splicing resulting in inclusion of intronic sequence (PMID: 24362817). For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome 2 Pathogenic:2

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3+PM3 -

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive Noonan syndrome 2 (MIM#605275). Dominant negative is the mechanism suspected for autosomal dominant Noonan syndrome 10 (MIM#616564). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR studies have demonstrated that this variant creates a cryptic splice acceptor site, leading to the retention of 11 intronic nucleotides and creating a frameshift (p. (Lys89Cysfs*16) that is expected to undergo nonsense-mediated decay (NMD) (PMID:24362817). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (24 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are many of these variants reported as pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported eight times in ClinVar as pathogenic, once as likely pathogenic and once as a variant of unknown significance. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Feb 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.264-13G>A intronic pathogenic mutation results from a G to A substitution 13 nucleotides upstream from coding exon 3 in the LZTR1 gene. This alteration has been identified in multiple individuals diagnosed with schwannomatosis and has been reported to segregate with disease in one family (Piotrowski A et al. Nat. Genet., 2014 Feb;46:182-7; Louvrier C et al. Neuro-oncology, 2018 06;20:917-929; Deiller C et al. Eur J Med Genet, 2019 Aug;62:103680). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies confirm that the predicted alternate splice acceptor site is utilized, resulting in the inclusion of 11 intronic nucleotides at the beginning of coding exon 3 and a frameshift (r.263_264ins264-11_264-1 p.K89Cfs*16) (Piotrowski A et al. Nat. Genet., 2014 Feb;46:182-7; Ambry internal data). This nucleotide position is not well conserved in available vertebrate species. 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. -

Schwannomatosis Pathogenic:1

Jun 12, 2024

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.264-13G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 3 acceptor site. Two predict the variant weakens a 3' acceptor site. Five predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Piotrowski_2014). The variant allele was found at a frequency of 4.4e-05 in 251194 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LZTR1 related diseases. c.264-13G>A has been reported in the literature in multiple individuals affected with Schwannomatosis (Piotrowski_2014, Alaidarous_2019, Deiller_2019, Louvrier_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, this variant has not been reported in patients with Noonan Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 24362817, 29409008, 27921248, 31438995, 31128261). ClinVar contains an entry for this variant (Variation ID: 101034). Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome 2;C3810283:LZTR1-related schwannomatosis;C4225280:Noonan syndrome 10 Pathogenic:1

Jan 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental disorder Uncertain:1

-

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	18
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 2
DS_AL_spliceai		0.86		Position offset: 13

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777176; hg19: chr22-21340117;