owencqueen/cgbench_data huggingface dataset:
Gene: MYOC (HGNC:7610)
Evidence Code: PVS1 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PS1 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PS1 — Strong
The novel change must not affect splicing (SpliceAI ≤ 0.2).
Gene: MYOC (HGNC:7610)
Evidence Code: PS1 — Moderate
Same amino acid change as a previously established likely pathogenic variant




The novel change must not affect splicing (SpliceAI ≤ 0.2).
Gene: MYOC (HGNC:7610)
Evidence Code: PS2 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PS2 — Strong
≥2 confirmed de novo in JOAG.
Use the proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.




Both maternity and paternity need to be proven for confirmed de novo variants.


Parents need to be clinically assessed and not have a diagnosis of glaucoma.
Gene: MYOC (HGNC:7610)
Evidence Code: PS2 — Moderate
≥2 confirmed de novo in POAG or 1 confirmed de novo in JOAG
Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.




Both maternity and paternity need to be proven for confirmed de novo variants.


Parents need to be clinically assessed and not have a diagnosis of glaucoma.
Gene: MYOC (HGNC:7610)
Evidence Code: PS2 — Supporting
1 confirmed de novo in POAG.
Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG. 




Both maternity and paternity need to be proven for confirmed de novo variants. 


Parents need to be clinically assessed and not have a diagnosis of glaucoma.
Gene: MYOC (HGNC:7610)
Evidence Code: PS3 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PS3 — Strong
Assays with OddsPath >18.7 as per the SVI recommendations.




Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.


PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.


If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.


Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.


If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.
Gene: MYOC (HGNC:7610)
Evidence Code: PS3 — Moderate
Assays with OddsPath >4.3 as per the SVI recommendations




Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.


PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.


If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.


Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.


If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.
Gene: MYOC (HGNC:7610)
Evidence Code: PS3 — Supporting
Assays with OddsPath >2.1 as per the SVI recommendations.




Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.


PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.


If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.


Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.


If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.
Gene: MYOC (HGNC:7610)
Evidence Code: PS4 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PS4 — Strong
≥ 15 probands from multiple independent studies.




Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.


PM2_Supporting must be met.
Gene: MYOC (HGNC:7610)
Evidence Code: PS4 — Moderate
≥ 6 probands from multiple independent studies.




Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.


PM2_Supporting must be met.
Gene: MYOC (HGNC:7610)
Evidence Code: PS4 — Supporting
≥ 2 probands from multiple independent studies.




Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.


PM2_Supporting must be met.
Gene: MYOC (HGNC:7610)
Evidence Code: PM1 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PM2 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PM2 — Supporting
Allele frequency ≤ 0.0001 in population databases.




The highest allele frequency in population databases should be used. 


Only applies to populations of ≥ 10,000 alleles.
Gene: MYOC (HGNC:7610)
Evidence Code: PM3 — Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase.
Gene: MYOC (HGNC:7610)
Evidence Code: PM4 — Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: MYOC (HGNC:7610)
Evidence Code: PM4 — Moderate
In-frame del/ins and truncating variants involving >10% of the protein and located within the conserved olfactomedin domain (AA 246-502).
Gene: MYOC (HGNC:7610)
Evidence Code: PM4 — Supporting
In-frame del/ins and truncating variants involving ≤10% of the protein and located within the conserved olfactomedin domain (AA 246-502).
Gene: MYOC (HGNC:7610)
Evidence Code: PM5 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PM5 — Moderate
Same residue as a previously established pathogenic variant (assessed independently of PM5) or 2 previously established likely pathogenic variants (both assessed independently of PM5)




The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3 and have a Grantham score equal or greater than the previously established P/LP variants.
Gene: MYOC (HGNC:7610)
Evidence Code: PM5 — Supporting
Same residue as a previously established likely pathogenic variant (assessed independently of PM5).




The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3 and have a Grantham score equal or greater than the previously established P/LP variants.
Gene: MYOC (HGNC:7610)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: MYOC (HGNC:7610)
Evidence Code: PM6 — Moderate
≥2 assumed de novo in JOAG.
Use proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.




Both maternity and paternity need to be proven for confirmed de novo variants.


Parents need to be clinically assessed and not have a diagnosis of glaucoma.
Gene: MYOC (HGNC:7610)
Evidence Code: PM6 — Supporting
≥2 assumed de novo in POAG or 1 assumed de novo in JOAG
Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.




Both maternity and paternity need to be proven for confirmed de novo variants.


Parents need to be clinically assessed and not have a diagnosis of glaucoma.
Gene: MYOC (HGNC:7610)
Evidence Code: PP1 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PP1 — Strong
≥7 meioses in >1 family.




BA1 and BS1 must not be met.


Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.


Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.
Gene: MYOC (HGNC:7610)
Evidence Code: PP1 — Moderate
≥ 5 meioses.




BA1 and BS1 must not be met.


Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.


Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.
Gene: MYOC (HGNC:7610)
Evidence Code: PP1 — Supporting
≥ 3 meioses.




BA1 and BS1 must not be met.


Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.


Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.
Gene: MYOC (HGNC:7610)
Evidence Code: PP2 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PP3 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: PP3 — Supporting
Applies to missense variants with a REVEL score of ≥ 0.7.
Gene: MYOC (HGNC:7610)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: MYOC (HGNC:7610)
Evidence Code: 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.
Gene: MYOC (HGNC:7610)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: MYOC (HGNC:7610)
Evidence Code: BA1 — Stand Alone
Allele frequency ≥ 0.01 in population databases.




The highest allele frequency in population databases should be used.


Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles.
Gene: MYOC (HGNC:7610)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: MYOC (HGNC:7610)
Evidence Code: BS1 — Strong
Allele frequency ≥ 0.001 in population databases.




The highest allele frequency in population databases should be used. 


Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles. 


Does not apply to p.Gln368Ter.
Gene: MYOC (HGNC:7610)
Evidence Code: BS2 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: MYOC (HGNC:7610)
Evidence Code: BS3 — Moderate
Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.23 as per the SVI recommendations.




Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.


If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.


Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.


If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.
Gene: MYOC (HGNC:7610)
Evidence Code: BS3 — Supporting
Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.48 as per the SVI recommendations.




Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.


If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.


Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.


If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.
Gene: MYOC (HGNC:7610)
Evidence Code: BS4 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: MYOC (HGNC:7610)
Evidence Code: BP2 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: MYOC (HGNC:7610)
Evidence Code: BP4 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: BP4 — Supporting
Applies to:




Missense variants with a REVEL score of ≤ 0.15.


Synonymous variants or noncoding variants with a CADD score of ≤ 10 AND SpliceAI ≤ 0.2
Gene: MYOC (HGNC:7610)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: MYOC (HGNC:7610)
Evidence Code: 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.
Gene: MYOC (HGNC:7610)
Evidence Code: BP7 — 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.
Gene: MYOC (HGNC:7610)
Evidence Code: BP7 — Supporting
Applies to synonymous variants or noncoding variants with no impact on splicing (SpliceAI ≤ 0.2) and GERP <0 for conservation.