Variant classification summary

NM_006767.4:c.2412dup

LZTR1 · NP_006758.2:p.(Lys805GlnfsTer46) · NM_006767.4

GRCh37: chr22:21351524 T>TC · GRCh38: chr22:20997235 T>TC

Gene: LZTR1 Transcript: NM_006767.4

Final call

VUS

PM2 supporting

Variant details

Gene

LZTR1

Transcript

NM_006767.4

Protein

NP_006758.2:p.(Lys805GlnfsTer46)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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%.

3

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.

4

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.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.3.0 v1.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not assessed	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.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This 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.	cspec
PS2	Not assessed	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.	cspec clinvar
PS3	Not assessed	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.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not assessed	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.	cspec clinvar gnomad_v2 gnomad_v4
PM1	N/A	PM1 is not applicable in the LZTR1 VCEP specification.	cspec
PM2	Met	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.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	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.	cspec
PM4	Not assessed	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.	cspec pvs1_variant_assessment
PM5	N/A	PM5 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.	cspec
PM6	Not assessed	No presumed de novo occurrence without confirmed parentage was identified for this variant, so PM6 cannot be assessed from the available evidence.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	cspec
PP2	N/A	PP2 is not applicable in the LZTR1 VCEP specification.	cspec
PP3	N/A	PP3 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.	cspec spliceai
PP4	N/A	PP4 is not applicable in the LZTR1 VCEP specification because the phenotype is not sufficiently specific to a single genetic etiology.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BA1	Not met	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.	cspec gnomad_v2 gnomad_v4
BS1	Not met	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.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No observations of this variant in well-characterized unaffected individuals were identified, so BS2 cannot be assessed.	cspec
BS3	N/A	BS3 is not applicable in the LZTR1 VCEP specification.	cspec
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 cannot be assessed.	cspec
BP1	N/A	BP1 is not applicable in the LZTR1 VCEP specification.	cspec
BP2	Not assessed	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.	cspec
BP3	N/A	BP3 is not applicable in the LZTR1 VCEP specification.	cspec
BP4	N/A	BP4 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.	cspec spliceai
BP5	Not assessed	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.	cspec
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	BP7 is intended for synonymous or certain non-coding variants with no predicted splice impact. This variant is a frameshift, so BP7 is not applicable.	cspec spliceai

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