About LZTR1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
LZTR1 c.2417T>G, p.(Leu806Trp)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen LZTR1 VCEP v1.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0 in both datasets. This satisfies the LZTR1 specification requirement for PM2 at Supporting strength because the variant is absent from population controls and is below the AR support threshold of 0.0025%.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
REVEL is 0.174, which is below the LZTR1 BP4 threshold of 0.3, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. BayesDel is also negative at -0.202983. These computational findings support no meaningful effect on protein function or splicing, so BP4 is met at Supporting strength.
Recorded classification: Uncertain significance
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.3.0 v1.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, BP4 supporting; no rule matched the adjudicated criteria.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. LZTR1, a ubiquitin ligase adaptor protein, is recurrently altered by mutation in glioblastoma, Noonan syndrome, and schwannomatosis.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen LZTR1 VCEP v1.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 12 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The LZTR1 c.2417T>G (p.Leu806Trp) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as likely pathogenic by a single clinical laboratory.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0 in both datasets.
Computational evidence supports a benign interpretation because REVEL is 0.174, below the LZTR1 BP4 threshold of 0.3, SpliceAI predicts no splice effect with a maximum delta score of 0.00, and BayesDel is -0.202983.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0 in both datasets. This satisfies the LZTR1 specification requirement for PM2 at Supporting strength because the variant is absent from population controls and is below the AR support threshold of 0.0025%. Details ▾Hide ▴
Rule
Supporting: variant absent from controls (gnomAD); for LZTR1, PM2_P ≤0.0025% may support AR disease.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BP4 SupportingREVEL is 0.174, which is below the LZTR1 BP4 threshold of 0.3, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. BayesDel is also negative at -0.202983. These computational findings support no meaningful effect on protein function or splicing, so BP4 is met at Supporting strength. Details ▾Hide ▴
Rule
Supporting for missense variants with REVEL ≤0.3.
Evidence considered
- REVEL 0.174
- SpliceAI max delta 0.00
- BayesDel -0.202983
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 This is a missense variant, not a null variant, and SpliceAI predicts no splice impact with a maximum delta score of 0.00. The LZTR1 specification directs PVS1 use for loss-of-function variants in the appropriate disease context, and the available evidence does not show a PVS1-eligible loss-of-function mechanism for this variant. Details ▾Hide ▴
Rule
Null variant in a gene where loss of function is a known mechanism of disease.
Evidence considered
- Missense change p.(Leu806Trp)/p.(L806W)
- SpliceAI max delta score 0.00
- Generic PVS1 scaffold does not place this variant in a null-variant bucket
Sources
PM4 This is a missense substitution and does not cause a protein length change from an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 is not met. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Variant is p.(Leu806Trp)
- a missense change
PP3 REVEL is 0.174, which is below the LZTR1 PP3 threshold of 0.7, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is -0.202983. Available computational evidence does not support a damaging effect for PP3. Details ▾Hide ▴
Rule
Supporting for missense variants with REVEL ≥0.7; for splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.174
- SpliceAI max delta 0.00
- BayesDel -0.202983
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0, which is below the BA1 threshold of 0.05%. BA1 is not met. Details ▾Hide ▴
Rule
Stand Alone if gnomAD filtering allele frequency ≥0.05%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0, which is below the BS1 threshold of 0.025%. BS1 is not met. Details ▾Hide ▴
Rule
Strong if gnomAD filtering allele frequency ≥0.025%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
Not assessed · 12 · no assessment recorded
PS1 No previously established pathogenic LZTR1 variant with the same amino acid change was identified in the available records, so PS1 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Still missing
- Direct confirmation of whether the same amino acid change has been established as pathogenic from an independent nucleotide change was not available.
PS2 No confirmed de novo occurrence with maternity and paternity confirmation was identified for this variant, so PS2 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
De novo in a patient with the disease and no family history; point-based scoring per RASopathy specification.
Still missing
- No case-level parental testing or phenotype-confirmed de novo data were available.
PS3 No approved variant-specific functional study was identified for this variant, so PS3 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
Supporting with one approved assay; Moderate with two or more different approved assays.
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
- RASopathy VCEP approved functional assay framework reviewed
Still missing
- Direct review of any future variant-specific approved assay data would be needed for PS3.
Sources
oncokb ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No published enrichment study, case series, or scored proband dataset was identified for this variant. A single ClinVar submitter does not establish the proband points required for PS4. Details ▾Hide ▴
PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive case, so PM3 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
For recessive disorders, scored by points when observed in trans with a pathogenic variant.
Evidence considered
- LZTR1 specification requires case-level inheritance assessment for PM3
Still missing
- Phase
- second-allele
- and inheritance data were not available.
Sources
PM5 No pathogenic or likely pathogenic missense change at codon 806 was identified in the available records, so PM5 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
Moderate with one pathogenic/likely pathogenic residue change at the same codon; Strong with ≥2 such changes observed in ≥5 probands.
Still missing
- Direct codon-level confirmation of previously established pathogenic residue changes at Leu806 was not available.
PM6 No assumed de novo observation without full parental confirmation was identified for this variant, so PM6 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
Point-based de novo scoring in conjunction with PS2 under the RASopathy specification.
Still missing
- No case-level inheritance data or partial de novo evidence were available.
PP1 No segregation data were identified for this variant, so PP1 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
Supporting ≥3 informative meioses; Moderate ≥5; Strong ≥7.
Evidence considered
- LZTR1 specification requires ≥3 informative meioses for PP1 Supporting
Still missing
- No pedigree data or informative meiosis counts were available.
Sources
BS2 No healthy carrier or unaffected adult observation meeting the LZTR1 phenotypic specifications was identified for this variant, so BS2 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
Strong at -4 points; Supporting at -1 point.
Evidence considered
- LZTR1 specification uses point-based BS2 scoring
Still missing
- No unaffected carrier data or point-based benign case data were available.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
Strong with lack of segregation in affected members of a family; requires one informative meiosis.
Evidence considered
- LZTR1 specification requires at least one informative meiosis for BS4
Still missing
- No informative family data were available.
Sources
BP2 No evidence was identified that this variant occurred with an alternative explained phenotype scenario or qualifying phase context under the RASopathy point-based benign framework, so BP2 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
Supporting at -1 point; Moderate at -2 points; Strong at -4 points.
Evidence considered
- LZTR1 specification uses point-based BP2 scoring
Still missing
- No case-level alternative diagnosis or phase data were available.
Sources
BP5 No evidence was identified for an alternative molecular explanation meeting the RASopathy benign point-based framework, so BP5 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
Supporting at -1 point; Moderate at -2 points; Strong at -4 points.
Evidence considered
- LZTR1 specification uses point-based BP5 scoring
Still missing
- No case-level alternative diagnosis data were available.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PM1 N/APM1 is marked not applicable in the LZTR1 specification, so it should not be used for this variant. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- LZTR1 specification lists PM1 as not applicable
Sources
PP2 N/APP2 is marked not applicable in the LZTR1 specification, so it should not be used for this variant. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- LZTR1 specification lists PP2 as not applicable
Sources
PP4 N/APP4 is marked not applicable in the LZTR1 specification, so it should not be used for this variant. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- LZTR1 specification lists PP4 as not applicable
Sources
PP5 N/APP5 is marked not applicable in the LZTR1 specification, so it should not be used for this variant. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- LZTR1 specification lists PP5 as not applicable
Sources
BS3 N/ABS3 is marked not applicable in the LZTR1 specification, so it should not be used for this variant. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- LZTR1 specification lists BS3 as not applicable
Sources
BP1 N/ABP1 is marked not applicable in the LZTR1 specification, so it should not be used for this variant. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- LZTR1 specification lists BP1 as not applicable
Sources
BP3 N/ABP3 is marked not applicable in the LZTR1 specification, so it should not be used for this variant. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- LZTR1 specification lists BP3 as not applicable
Sources
BP6 N/ABP6 is marked not applicable in the LZTR1 specification, so it should not be used for this variant. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- LZTR1 specification lists BP6 as not applicable
Sources
BP7 N/AThis is a missense variant rather than a synonymous, intronic, or non-coding variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
Applicable to synonymous, certain intronic, or non-coding variants with no predicted splice impact.
Evidence considered
- Variant is p.(Leu806Trp)
- a missense change
Sources
Identifiers
- Gene
- LZTR1
- Transcript
- NM_006767.4
- Coding (HGVS c.)
- NM_006767.4:c.2417T>G
- Protein (HGVS p.)
- NP_006758.2:p.(Leu806Trp)
- GRCh38
- chr22:20997242 T>G
- GRCh37
- chr22:21351531 T>G
Gene diagram
Every interpreted variant in LZTR1, mapped onto the exon structure of NM_006767.4. Select a row to find it on the plot.
LZTR1NM_006767.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in LZTR1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingREVEL is 0.174, which is below the LZTR1 BP4 threshold of 0.3, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. BayesDel is also negative at -0.202983. These computational findings support no meaningful effect on protein function or splicing, so BP4 is met at Supporting strength. Details ▾Hide ▴
Rule
Supporting for missense variants with REVEL ≤0.3.
Evidence considered
- REVEL 0.174
- SpliceAI max delta 0.00
- BayesDel -0.202983
Sources
PP3 REVEL is 0.174, which is below the LZTR1 PP3 threshold of 0.7, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is -0.202983. Available computational evidence does not support a damaging effect for PP3. Details ▾Hide ▴
Rule
Supporting for missense variants with REVEL ≥0.7; for splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.174
- SpliceAI max delta 0.00
- BayesDel -0.202983
Sources
BP7 N/AThis is a missense variant rather than a synonymous, intronic, or non-coding variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
Applicable to synonymous, certain intronic, or non-coding variants with no predicted splice impact.
Evidence considered
- Variant is p.(Leu806Trp)
- a missense change
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.174. BayesDel score = -0.202983.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1532496138
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1489825/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-21351531-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-20997242-T-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006767.4%3Ac.2417…
- OncoKB ↗www.oncokb.org/gene/LZTR1/L806W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=LZTR1+c.2417T%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.174. BayesDel score = -0.202983.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. LZTR1, a ubiquitin ligase adaptor protein, is recurrently altered by mutation in glioblastoma, Noonan syndrome, and schwannomatosis.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.