Criteria Specification Registry

Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.

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Criteria Specification

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.0.0

Description : These are the ACMG/AMP variant classification specifications developed by the RASopathy VCEP for LZTR1.

Version : 1.0.0 Release Notes :

This is a step 2 submission for classification rules review/approval, but I am only being given the option to submit pilot rules.

RASopathy VCEP

Released

8/3/2024

01:08:09

Rules for LZTR1

Gene: LZTR1 (HGNC:6742) HGNC Name: leucine zipper like transcription regulator 1 Transcripts: NM_006767.4 Disease: RASopathy (MONDO:0021060) Mode of Inheritance: Autosomal recessive inheritance, Autosomal dominant inheritance

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. Stand Alone Very Strong Null variant in a gene where loss of function is a known mechanism of disease. Modification Type: Disease-specific,Gene-specific Strong Null variant in a gene where loss of function is a known mechanism of disease. Modification Type: Disease-specific,Gene-specific,Strength Moderate Null variant in a gene where loss of function is a known mechanism of disease. Modification Type: Disease-specific,Gene-specific,Strength Supporting Null variant in a gene where loss of function is a known mechanism of disease. Modification Type: Disease-specific,Gene-specific,Strength Instructions: Follow SVI recommendations for application. This rule can be applied when curating for AR disease only. Please reference the attached, LZTR1-specific PVS1 Decision Tree before applying PVS1. Not Applicable Comments: Not applicable.
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Same amino acid change as a previously established pathogenic variant in LZTR1 regardless of nucleotide change. Modification Type: No change Moderate Supporting Instructions: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone Very Strong 4 Points. Modification Type: Strength Strong 2 Points. Modification Type: None Moderate 1 Point. Modification Type: Strength Supporting Instructions: Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points (1 point) awarded with RASopathy phenotypes, reduced points (0.5 points) applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)). Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. Stand Alone Very Strong Strong Moderate Two or more different approved assays. Modification Type: Gene-specific,Strength Supporting One approved assay. Modification Type: Gene-specific,Strength Instructions: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays for PS3 usage are available in the supplemental materials. Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. Stand Alone Very Strong Strong ≥5 points. Modification Type: Disease-specific Moderate ≥3 points. Modification Type: Strength Supporting ≥1 points. Modification Type: Strength Instructions: Please reference the Case Level Inheritance Flowchart before applying PS4. Dominant-negative variants: Strength adjustment using point-based scoring for autosomal dominant cases with RASopathy phenotypic specifications: full points (1) awarded with consistent RASopathy phenotype (See Table 1 in PMID: 30311384), reduced points (0.5) applicable to cases with minimal phenotypic information including prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES). Phenotypes for prenatal cases include hypertrophic cardiomyopathy, increased nuchal translucency, cystic hygroma, or hydrops. OR Dominant loss-of-function variants: Usage of this rule is case specific based on the inheritance of the variant and only PS4 OR PM3 can be applied to a single case. 1 point awarded for autosomal dominant cases with isolated schwannomatosis consistent with the loss-of-function disease mechanism. Loss-of-function variants observed in cases with autosomal recessive NS should only be counted using PM3. Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Moderate Supporting Instructions: Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Not Applicable Comments: Not applicable at this time.
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Supporting The variant must be absent from controls (gnomAD). For variants in LZTR1, PM2_P ≤0.0025% may be applied to support AR disease. Modification Type: Disease-specific,Gene-specific,Strength Instructions: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong ≥4 points. Modification Type: Disease-specific,Gene-specific,Strength Strong ≥2 points. Modification Type: Disease-specific,Gene-specific,Strength Moderate ≥1 points. Modification Type: Disease-specific,Gene-specific Supporting ≥0.5 points. Modification Type: Disease-specific,Gene-specific,Strength Instructions: Please reference the Case Level Inheritance Flowchart before applying PM3. Usage of this rule is case specific based on the inheritance of the variant and only PS4 OR PM3 can be applied to a single case. Cases with autosomal recessive NS are scored using PM3, as defined by SVI. Cases with autosomal dominant isolated schwannomatosis should be counted using PS4. Not Applicable Comments: Not applicable.
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong Moderate No known repetitive areas in gene. Use as described. Modification Type: General recommendation Supporting Instructions: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong ≥2 different [likely] pathogenic residue changes at the same codon observed in ≥5 probands. Modification Type: Strength Moderate 1 [likely] pathogenic residue change at the same codon observed in ≥5 probands. Modification Type: Disease-specific Supporting Instructions: Applicable for observed analogous residue positions in LZTR1. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5_Strong is applied to avoid overweighting. Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Strong 2 Points. Modification Type: Strength Moderate 1 Point. Modification Type: None Supporting 0.5 Points. Modification Type: Strength Instructions: Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)). Not Applicable
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. Stand Alone Very Strong Strong ≥7 informative meioses. Modification Type: Strength Moderate ≥5 informative meioses. Modification Type: Strength Supporting ≥3 informative meioses. Modification Type: Disease-specific Instructions: Segregation in more than one family is recommended. Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Not applicable because missense z score is <3.09 in gnomAD.
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism. Modification Type: Disease-specific Instructions: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: PP4 is not applicable due to genetic heterogeneity.
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone GnomAD filtering allele frequency ≥0.05%. Modification Type: Disease-specific Very Strong Strong Moderate Supporting Instructions: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Standard LoF variants should be assessed for effect via PVS1 before applying BA1/BS1 as new population data becomes available. See exceptions for higher frequency LoF variants in LZTR1. Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong GnomAD filtering allele frequency ≥0.025%. Modification Type: Disease-specific Moderate Supporting Instructions: Allele frequency is greater than expected for disorder. Standard LoF variants should be assessed for effect via PVS1 before applying BA1/BS1 as new population data becomes available. See exceptions for higher frequency LoF variants in LZTR1. Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Stand Alone Very Strong Strong -4 Points. Modification Type: Strength Moderate Supporting -1 Point. Modification Type: Strength Instructions: Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations. Not Applicable
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong Moderate Supporting Instructions: Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Not Applicable Comments: Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong Requires only one informative meiosis. Modification Type: General recommendation Moderate Supporting Instructions: Lack of segregation in affected members of a family. Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants. Modification Type: Disease-specific Instructions: Missense variant in a gene for which primarily truncating variants are known to cause disease. Not Applicable
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong ≥ (-4) Points. Modification Type: Strength Moderate ≥ (-2) Points. Modification Type: Strength Supporting ≥ (-1) Point. Modification Type: None Instructions: For each case, -1 point applies when phenotype inconsistent with a RASopathy and causative variant has been identified (ex. WES cases) OR alternative molecular cause of a RASopathy and the phenotype is consistent with expected severity of the RASopathy in the same gene (and/or in conjunction with BP5 in a different gene). Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: No known benign repetitive areas in RASopathy genes.
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting For missense variants: REVEL ≤0.3. Modification Type: Disease-specific Instructions: For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism. Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong ≥ (-4) Points. Modification Type: Strength Moderate ≥ (-2) Points. Modification Type: Strength Supporting ≥ (-1) Point. Modification Type: None Instructions: For each case, -1 point applies when phenotype inconsistent with a RASopathy and causative variant has been identified (ex. WES cases) OR alternative molecular cause of a RASopathy and the phenotype is consistent with expected severity of the RASopathy in a different gene (and/or in conjunction with BP2 in the same gene). Not Applicable
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4. Modification Type: General recommendation Instructions: A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PS4, PM3_Strong, PM5_Strong, PM6_Strong, PP1_Strong)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 2 Moderate (PVS1_Moderate, PS2_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS2_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate) AND 1 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3)

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS4, PM3_Strong, PM5_Strong, PM6_Strong, PP1_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS4, PM3_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS2_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS4, PM3_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS2_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3)

1 Strong (PVS1_Strong, PS1, PS2, PS4, PM3_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS2_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3)

Likely Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS2_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS4, PM3_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS2_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS4, PM3_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3)

≥ 3 Moderate (PVS1_Moderate, PS2_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate)

2 Moderate (PVS1_Moderate, PS2_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3)

1 Moderate (PVS1_Moderate, PS2_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3)

Benign

≥ 2 Strong (BS1, BS2, BS4, BP2_Strong, BP5_Strong)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS4, BP2_Strong, BP5_Strong) AND 1 Supporting (BS2_Supporting, BP1, BP2, BP4, BP5, BP7)

≥ 2 Supporting (BS2_Supporting, BP1, BP2, BP4, BP5, BP7)

1 Strong (BS1, BS2, BS4, BP2_Strong, BP5_Strong)

1 Strong (BS1)

Files & Images

Case Level Inheritance Flowchart: This documentation specifies how to determine the inheritance pattern of variants in LZTR1. It then indicates which ACMG/AMP criteria can be applied to AD vs. AR variants in LZTR1.

PVS1 Decision Tree: This documentation specifies how to apply PVS1 to variants in LZTR1.

References

1. https://clinicalgenome.org/site/assets/files/3461/svi_proposal_for_de_novo_criteria_v1_1.pdf

2. https://docs.google.com/spreadsheets/d/1PuOwrvjGIDvAIPdfARdApg5FUl_H8REf/edit#gid=1702220162

3. https://docs.google.com/spreadsheets/d/18p8vjFMIDPkxEZl5ghZ1vOy8pYKy1G1fRnJOcSsfXgE/edit#gid=717223407