rs587777176

Positions:

• chr22-20985828-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_006767.4(LZTR1):​c.264-13G>A variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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/exons	MANE	Protein	UniProt
LZTR1	NM_006767.4	c.264-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000646124.2	NP_006758.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2	c.264-13G>A		splice_polypyrimidine_tract_variant, intron_variant			NM_006767.4	ENSP00000496779	P1

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:11 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2024	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	LZTR1: PS3:Moderate, PS4:Moderate, PM2:Supporting, PP1, PP3 -

Schwannomatosis 2 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 21, 2024	PS3_Very Strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 23, 2023	- -

Noonan syndrome 2;C3810283:Schwannomatosis 2;C4225280:Noonan syndrome 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 20, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 12, 2024

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. -

Developmental disorder Uncertain:1

Uncertain significance, flagged submission

clinical testing

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

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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;