Variant classification summary

NM_006767.4:c.2417T>G

LZTR1 · NP_006758.2:p.(Leu806Trp) · NM_006767.4

GRCh37: chr22:21351531 T>G · GRCh38: chr22:20997242 T>G

Gene: LZTR1 Transcript: NM_006767.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

LZTR1

Transcript

NM_006767.4

Protein

NP_006758.2:p.(Leu806Trp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0 in both datasets.

3

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.

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 met	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.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	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.
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity confirmation was identified for this variant, so PS2 cannot be applied from the current evidence.
PS3	Not assessed	No approved variant-specific functional study was identified for this variant, so PS3 cannot be applied from the current evidence.	oncokb vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	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.	clinvar cspec
PM1	N/A	PM1 is marked not applicable in the LZTR1 specification, so it should not be used for this variant.	cspec
PM2	Met	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%.	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 applied from the current evidence.	cspec
PM4	Not met	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.
PM5	Not assessed	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.
PM6	Not assessed	No assumed de novo observation without full parental confirmation was identified for this variant, so PM6 cannot be applied from the current evidence.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied from the current evidence.	cspec
PP2	N/A	PP2 is marked not applicable in the LZTR1 specification, so it should not be used for this variant.	cspec
PP3	Not met	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.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is marked not applicable in the LZTR1 specification, so it should not be used for this variant.	cspec
PP5	N/A	PP5 is marked not applicable in the LZTR1 specification, so it should not be used for this variant.	cspec
BA1	Not met	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.	cspec gnomad_v2 gnomad_v4
BS1	Not met	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.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	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.	cspec
BS3	N/A	BS3 is marked not applicable in the LZTR1 specification, so it should not be used for this variant.	cspec
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be applied from the current evidence.	cspec
BP1	N/A	BP1 is marked not applicable in the LZTR1 specification, so it should not be used for this variant.	cspec
BP2	Not assessed	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.	cspec
BP3	N/A	BP3 is marked not applicable in the LZTR1 specification, so it should not be used for this variant.	cspec
BP4	Met	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.	cspec revel spliceai bayesdel
BP5	Not assessed	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.	cspec
BP6	N/A	BP6 is marked not applicable in the LZTR1 specification, so it should not be used for this variant.	cspec
BP7	N/A	This is a missense variant rather than a synonymous, intronic, or non-coding variant, so BP7 is not applicable.	cspec

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