rs761685529

chr22-20995490-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4

The NM_006767.4(LZTR1):c.1943-256C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000792 in 668,844 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 Conflicting classifications of pathogenicity (no stars).

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

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1

Conservation

PhyloP100: -0.680

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 Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 22-20995490-C-T is Pathogenic according to our data. Variant chr22-20995490-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522800.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Uncertain_significance=1}.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LZTR1	NM_006767.4 linkuse as main transcript	c.1943-256C>T		intron_variant		ENST00000646124.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LZTR1	ENST00000646124.2 linkuse as main transcript	c.1943-256C>T		intron_variant			NM_006767.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000791

AC:

AN:

151688

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000407

AC:

AN:

147296

Hom.:

AF XY:

0.0000376

AC XY:

AN XY:

79730

show subpopulations

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 SAS exome

AF:

0.0000881

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000362

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000793

AC:

AN:

517156

Hom.:

Cov.:

AF XY:

0.0000822

AC XY:

AN XY:

279928

show subpopulations

Gnomad4 AFR exome

AF:

0.0000683

Gnomad4 AMR exome

AF:

0.0000309

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000357

Gnomad4 SAS exome

AF:

0.0000810

Gnomad4 FIN exome

AF:

0.0000696

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.0000360

GnomAD4 genome

AF:

0.0000791

AC:

AN:

151688

Hom.:

Cov.:

AF XY:

0.0000810

AC XY:

AN XY:

74078

show subpopulations

Gnomad4 AFR

AF:

0.000170

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000949

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000907

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Noonan syndrome 2

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 11, 2022	Variant summary: LZTR1 c.1943-256C>T is located within intron 16 at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic 5' donor site. At least two publications report experimental evidence that this variant indeed affects mRNA splicing, resulting in the inclusion of the additional 117 bp cryptic exon between exons 16 and 17 (e.g. Johnston_2018, Hanses_2020). The variant allele was found at a frequency of 4.1e-05 in 147296 control chromosomes (gnomAD). c.1943-256C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Noonan Syndrome 2 from at least five different families in which the variant was found to segregate with the disease in an autosomal recessive pattern of inheritance (e.g. Johnston_2018, Hanses_2020). These data indicate that the variant is very likely to be associated with disease. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as pathogenic (n=3) and one classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous c.1943-256C>T variant in LZTR1 was identified by our study in the compound heterozygous state, along with another likely pathogenic variant, in 2 siblings with Noonan syndrome 2. The variant has been reported in 8 individuals of unknown ethnicity with Noonan syndrome 2 (PMID: 29469822, 32623905) and segregated with disease in 4 affected relatives from 3 families (PMID: 29469822, 32623905). This variant has been identified in 0.019% (3/15796) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs761685529). Although the c.1943-256C>T variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 522800) as pathogenic by OMIM and GeneDx, and as having unknown significance by the Undiagnosed Diseases Network, NIH. Of the 10 affected individuals, 2 of those were homozygotes, 5 were compound heterozygotes that carried a reported pathogenic/likely pathogenic variants in trans, and 3 were compound heterozygotes that carried a variants of uncertain significance in trans, which increases the likelihood that the c.1943-256C>T variant is pathogenic (VariationID: 522799, 372684; PMID: 29469822, 32623905). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 29469822, 32623905). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Noonan syndrome 2. ACMG/AMP Criteria applied: PM3_strong, PP1_strong, PS3_moderate (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	May 01, 2017	This family has been reported in PMID:29469822. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 17, 2018	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2022	Non-canonical splice site variant demonstrated to result in loss-of-function; inclusion of 117bp from an alternate exon lead to a truncated protein, p.(T648fs*36), that was subject to nonsense mediated decay (Johnston et al., 2018; Hanses et al. 2020); This variant is associated with the following publications: (PMID: 29469822, 32623905, 34747535) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change falls in intron 16 of the LZTR1 gene. It does not directly change the encoded amino acid sequence of the LZTR1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs761685529, gnomAD 0.02%). This variant has been observed in individuals with Noonan syndrome (PMID: 29469822, 32623905). ClinVar contains an entry for this variant (Variation ID: 522800). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 29469822, 32623905). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant has been previously reported as a homozygous and compound heterozygous change in individuals with Noonan syndrome and shown to moderately segregate with disease in two families (PMID: 29469822). Heterozygous carrier parents demonstrated mild or no clinical manifestations (PMID: 29469822). Splicing studies using the RNA from a patient's lymphoblasts showed an abnormal product retaining a 117bp sequence from intron 16 (PMID: 29469822). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (11/178598) and is absent in the homozygous state, and thus is presumed to be rare. Based on the available evidence, the c.1943-256C>T variant is classified as Pathogenic. -

Schwannomatosis 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 23, 2023

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The c.1943-256C>T intronic pathogenic mutation results from a C to T substitution 256 nucleotides upstream from coding exon 17 in the LZTR1 gene. This alteration has been reported in multiple individuals with autosomal recessive Noonan syndrome in trans with other mutations or in the homozygous state and was shown to segregate with disease in several families (Johnston JJ et al. Genet Med. 2018 Oct;20(10):1175-1185). RNA studies demonstrated that this alteration results in the retention of a 117-base pair alternate exon that lies within intron 16 (Johnston JJ et al. Genet Med. 2018 Oct;20(10):1175-1185; Hanses U et al. Circulation, 2020 Sep;142:1059-1076; Ambry internal data). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

Cadd

Benign

Dann

Benign

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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

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