About LZTR1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
LZTR1 c.2412dup, p.(Lys805GlnfsTer46)
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the LZTR1 VCEP specification, absence from controls meets PM2 at Supporting strength for variants used to support autosomal recessive disease, and the observed frequency is below the ≤0.0025% threshold.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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; 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.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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: 1 met · 2 not met · 12 not assessed · 13 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.2412dup (p.Lys805GlnfsTer46; p.K805Qfs*46) variant has not been observed in COSMIC and has been reported in ClinVar with likely pathogenic and pathogenic submissions.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting the LZTR1 PM2_Supporting threshold of ≤0.0025%.
OncoKB classifies this variant as likely oncogenic with a likely loss-of-function biological effect, but no approved RASopathy VCEP functional assay result was identified for this specific variant.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, and no REVEL or BayesDel score was available because this is not a single-nucleotide variant.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the LZTR1 VCEP specification, absence from controls meets PM2 at Supporting strength for variants used to support autosomal recessive disease, and the observed frequency is below the ≤0.0025% threshold. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD). For variants in LZTR1, PM2_P ≤0.0025% may be applied to support AR disease.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- LZTR1 VCEP PM2 threshold is ≤0.0025% for PM2_Supporting.
Still missing
- Phenotype and inheritance context are still needed for downstream combination-rule interpretation.
Sources
Not met · 2 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 threshold of ≥0.05%, so BA1 is not met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- BA1 threshold is ≥0.05%.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 threshold of ≥0.025%, so BS1 is not met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- BS1 threshold is ≥0.025%.
Sources
Not assessed · 12 · no assessment recorded
PVS1 This variant is a frameshift in LZTR1, and loss of function is an established disease mechanism in the LZTR1 VCEP framework. However, the LZTR1 specification states that PVS1 should be applied only when curating autosomal recessive disease, and this C-terminal frameshift occurs in the final exon with replacement of the last 37 amino acids by 46 novel amino acids, so available evidence does not support assigning a PVS1 strength without phenotype- and mechanism-specific review. Details ▾Hide ▴
Rule
Follow SVI recommendations for application. This rule can be applied when curating for AR disease only.
Evidence considered
- LZTR1 VCEP framework includes PVS1 guidance.
- Gene-level PVS1 gate is eligible.
- Variant is a terminal-exon frameshift with predicted altered C-terminus rather than a clearly NMD-triggering truncation.
Still missing
- Confirm the relevant disease context and inheritance model for this case before applying PVS1.
- Confirm whether this terminal-exon frameshift should be treated as a typical loss-of-function variant or an atypical C-terminal altered-protein event under the LZTR1-specific PVS1 decision tree.
Sources
PS2 No confirmed de novo occurrence with documented maternity and paternity testing was identified for this variant, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
4 points = Very Strong; 2 points = Strong; 1 point = Moderate.
Evidence considered
- ClinVar summary does not provide confirmed de novo evidence for this variant.
Still missing
- Variant-specific case reports with confirmed de novo status and phenotype details were not identified.
Sources
PS3 Approved RASopathy VCEP functional assay types are available for LZTR1, but no variant-specific approved functional study for NM_006767.4:c.2412dup was identified. OncoKB describes the variant as likely loss-of-function, but this does not substitute for an approved variant-specific PS3 assay in the VCEP framework. Details ▾Hide ▴
Rule
Two or more different approved assays = Moderate; one approved assay = Supporting.
Evidence considered
- Approved assay list includes LZTR1 stability/localization assays.
- OncoKB classifies the variant as likely oncogenic with likely loss-of-function biological effect.
Still missing
- No variant-specific approved functional assay result was identified for this exact variant.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesoncokb ↗PMID:23917401 ↗PMID:24362817 ↗PMID:30442762 ↗PMID:30872527 ↗PMID:36445254 ↗
PS4 This variant has been reported in ClinVar, but no case-level point count or affected-versus-control enrichment data were identified to meet the LZTR1 VCEP PS4 thresholds. The variant is absent from gnomAD, but the available evidence does not establish the required number of scored affected observations. Details ▾Hide ▴
Rule
≥5 points = Strong; ≥3 points = Moderate; ≥1 point = Supporting.
Evidence considered
- ClinVar contains pathogenic and likely pathogenic submissions.
- Variant is absent from gnomAD v2.1 and v4.1.
Still missing
- No variant-specific proband count with sufficient phenotype detail was identified.
- No case-level PS4 point calculation was available.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive case, so PM3 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
PM3 is case specific based on inheritance; only PS4 or PM3 can be applied to a single case.
Evidence considered
- PM3 in LZTR1 is case-specific and depends on recessive observations with phase information.
Still missing
- No phasing data or recessive case-level observations were identified for this variant.
Sources
PM4 This variant alters the C-terminal protein length, replacing the final 37 amino acids with 46 novel amino acids and extending the protein by 9 amino acids overall. However, the LZTR1 VCEP PM4 rule is written for in-frame deletions/insertions and stop-loss variants, so it is unclear from the available evidence whether this terminal frameshift should be counted under PM4 without manual review. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Predicted protein consequence p.(Lys805GlnfsTer46).
- PM4 rule is defined for protein length changes due to in-frame indels or stop-loss variants.
Still missing
- Confirm whether this C-terminal frameshift fits the intended PM4 use in the LZTR1 framework.
Sources
cspec ↗pvs1_variant_assessment
PM6 No presumed de novo occurrence without confirmed parentage was identified for this variant, so PM6 cannot be assessed from the available evidence. Details ▾Hide ▴
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
≥7 informative meioses = Strong; ≥5 = Moderate; ≥3 = Supporting.
Evidence considered
- PP1 requires informative segregation data.
Still missing
- No family-based informative meioses were identified for this variant.
Sources
BS2 No observations of this variant in well-characterized unaffected individuals were identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
-4 points = Strong; -1 point = Supporting.
Evidence considered
- BS2 requires unaffected observations scored by the VCEP point framework.
Still missing
- No healthy adult or unaffected carrier data were identified for this variant.
Sources
BS4 No lack-of-segregation data were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- BS4 requires at least one informative meiosis showing lack of segregation.
Still missing
- No pedigree data showing non-segregation were identified for this variant.
Sources
BP2 No evidence was identified that this variant was observed in cis with a pathogenic variant or in a case with an alternative established molecular cause under the VCEP point framework, so BP2 cannot be assessed. Details ▾Hide ▴
Rule
≥-4 points = Strong; ≥-2 points = Moderate; ≥-1 point = Supporting.
Evidence considered
- BP2 requires case-level point-based evidence.
Still missing
- No phase data or alternative-cause case scoring was identified.
Sources
BP5 No evidence was identified that this variant was found with an alternate molecular explanation for the phenotype under the VCEP point framework, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
≥-4 points = Strong; ≥-2 points = Moderate; ≥-1 point = Supporting.
Evidence considered
- BP5 requires case-level evidence for an alternate molecular basis for disease.
Still missing
- No alternate-cause case data were identified for this variant.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis criterion applies to the same amino acid change as a previously established pathogenic variant. This variant is a frameshift and no evidence was identified that it produces the same amino acid change as an established pathogenic variant. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant in LZTR1 regardless of nucleotide change.
Evidence considered
- PS1 is defined for the same amino acid change regardless of nucleotide change.
Sources
PM1 N/APM1 is not applicable in the LZTR1 VCEP specification. Details ▾Hide ▴
PM5 N/APM5 is intended for a novel missense change at a residue where a different pathogenic missense change has been seen. This variant is a frameshift, so PM5 is not applicable. Details ▾Hide ▴
Rule
1 likely pathogenic/pathogenic residue change at the same codon = Moderate; ≥2 different changes in ≥5 probands = Strong.
Evidence considered
- PM5 is defined for analogous residue changes and missense substitutions.
Sources
PP2 N/APP2 is not applicable in the LZTR1 VCEP specification. Details ▾Hide ▴
PP3 N/APP3 in the LZTR1 VCEP specification is used for missense variants with REVEL ≥0.7 or for splice predictions that support the disease mechanism. This variant is not a missense change, REVEL and BayesDel were not available because it is not an SNV, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.02, so PP3 is not applicable. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL not available for this non-SNV.
- BayesDel not available for this non-SNV.
- SpliceAI max delta score is 0.02 with no significant predicted splice impact.
Sources
PP4 N/APP4 is not applicable in the LZTR1 VCEP specification because the phenotype is not sufficiently specific to a single genetic etiology. Details ▾Hide ▴
PP5 N/APP5 is not used in this VCEP framework. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in the LZTR1 VCEP specification. Details ▾Hide ▴
Evidence considered
- VCEP marks BS3 as not applicable.
Sources
BP1 N/ABP1 is not applicable in the LZTR1 VCEP specification. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the LZTR1 VCEP specification. Details ▾Hide ▴
BP4 N/ABP4 in the LZTR1 VCEP specification is used for missense variants with REVEL ≤0.3 or for splice variants with negligible predicted effect. This variant is a protein-altering frameshift, REVEL and BayesDel were not available because it is not an SNV, and the low SpliceAI score of 0.02 does not convert this frameshift into a BP4-eligible variant type, so BP4 is not applicable. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- REVEL not available for this non-SNV.
- BayesDel not available for this non-SNV.
- SpliceAI max delta score is 0.02.
Sources
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous or certain non-coding variants with no predicted splice impact. This variant is a frameshift, so BP7 is not applicable. Details ▾Hide ▴
Rule
A synonymous or certain intronic/non-coding variant with no predicted splice impact may be used with BP4.
Evidence considered
- Variant is a frameshift.
- SpliceAI shows no significant splice effect
- but BP7 is restricted to synonymous
- intronic
- or non-coding variants.
Sources
Identifiers
- Gene
- LZTR1
- Transcript
- NM_006767.4
- Coding (HGVS c.)
- NM_006767.4:c.2412dup
- Protein (HGVS p.)
- NP_006758.2:p.(Lys805GlnfsTer46)
- GRCh38
- chr22:20997235 T>TC
- GRCh37
- chr22:21351524 T>TC
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
PP3 N/APP3 in the LZTR1 VCEP specification is used for missense variants with REVEL ≥0.7 or for splice predictions that support the disease mechanism. This variant is not a missense change, REVEL and BayesDel were not available because it is not an SNV, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.02, so PP3 is not applicable. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL not available for this non-SNV.
- BayesDel not available for this non-SNV.
- SpliceAI max delta score is 0.02 with no significant predicted splice impact.
Sources
BP4 N/ABP4 in the LZTR1 VCEP specification is used for missense variants with REVEL ≤0.3 or for splice variants with negligible predicted effect. This variant is a protein-altering frameshift, REVEL and BayesDel were not available because it is not an SNV, and the low SpliceAI score of 0.02 does not convert this frameshift into a BP4-eligible variant type, so BP4 is not applicable. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- REVEL not available for this non-SNV.
- BayesDel not available for this non-SNV.
- SpliceAI max delta score is 0.02.
Sources
BP7 N/ABP7 is intended for synonymous or certain non-coding variants with no predicted splice impact. This variant is a frameshift, so BP7 is not applicable. Details ▾Hide ▴
Rule
A synonymous or certain intronic/non-coding variant with no predicted splice impact may be used with BP4.
Evidence considered
- Variant is a frameshift.
- SpliceAI shows no significant splice effect
- but BP7 is restricted to synonymous
- intronic
- or non-coding variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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/1176008/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-21351524-T-TC?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-20997235-T-TC?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006767.4%3Ac.2412…
- OncoKB ↗www.oncokb.org/gene/LZTR1/K805Qfs*46
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=LZTR1+c.2412dup
- 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 (2 clinical laboratories) and as Pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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.