Classification rationale

PM2 VUS

LZTR1 c.2412dup

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.¹ 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%.² 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.³ 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.⁴

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 oncokb ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies

4 spliceai ↗

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.

Gene diagram · NM_006767.4 · variants mapped to exon structure

LZTR1 NM_006767.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

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.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.LZTR1 VCEP PM2 threshold is ≤0.0025% for PM2_Supporting.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 2 not met · 12 not assessed

Pathogenic

PVS1 This variant is a frameshift in LZTR1, and loss of function is an established disease mechanism in the LZTR1 VCEP framework.

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.

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.

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.

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.

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.

PM6 No presumed de novo occurrence without confirmed parentage was identified for this variant, so PM6 cannot be assessed from the available evidence.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed.

Benign

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.

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.

BS2 No observations of this variant in well-characterized unaffected individuals were identified, so BS2 cannot be assessed.

BS4 No lack-of-segregation data were identified for this variant, so BS4 cannot be assessed.

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.

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.

N/A · 13 PS1 · PM1 · PM5 · PP2 · PP3 · PP4 · PP5 · BS3 · BP1 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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