rs777243508
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_006767.4(LZTR1):c.1407G>A(p.Trp469Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,612,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00017 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000058 ( 0 hom. )
Consequence
LZTR1
NM_006767.4 stop_gained
NM_006767.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.76
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 22-20993977-G-A is Pathogenic according to our data. Variant chr22-20993977-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 549753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LZTR1 | NM_006767.4 | c.1407G>A | p.Trp469Ter | stop_gained | 13/21 | ENST00000646124.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LZTR1 | ENST00000646124.2 | c.1407G>A | p.Trp469Ter | stop_gained | 13/21 | NM_006767.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152258Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000138 AC: 34AN: 246400Hom.: 0 AF XY: 0.000150 AC XY: 20AN XY: 133646
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GnomAD4 exome AF: 0.0000582 AC: 85AN: 1460092Hom.: 0 Cov.: 34 AF XY: 0.0000565 AC XY: 41AN XY: 726298
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GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152376Hom.: 0 Cov.: 34 AF XY: 0.000282 AC XY: 21AN XY: 74518
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 18, 2022 | This variant is present in population databases (rs777243508, gnomAD 0.1%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 549753). This premature translational stop signal has been observed in individual(s) with milder Noonan syndrome-like features (PMID: 30859559). This sequence change creates a premature translational stop signal (p.Trp469*) 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, 30442762, 30442766, 30481304, 30859559). - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 31, 2023 | The p.W469* pathogenic mutation (also known as c.1407G>A), located in coding exon 13 of the LZTR1 gene, results from a G to A substitution at nucleotide position 1407. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This variant has been reported in an individual with Noonan syndrome-like features including severe hypertrophic cardiomyopathy; it was confirmed in trans with an LZTR1 missense variant (c.2246A>G, p.Y749C) that was classified as a variant of unknown significance by authors (Pagnamenta AT et al. Clin Genet, 2019 Jun;95:693-703; Farncombe KM et al. BMC Med Genomics, 2022 Jul;15:160). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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 | research | Genomic Medicine Theme, NIHR Oxford Biomedical Research Centre, University of Oxford | Jul 02, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at