ACMGv4 Case Schema and Attribute Matrix¶

Superset Case Schema¶

{
  // General (all cases)
  "case_id": "string",
  "moi": "AD|AR|SD|XLD|XLR",
  "zygosity": "string",
  "mde_affected": "T|F|U",
  "well_phenotyped": "T|F|U",

  // UAF-specific
  "age_matched_penetrance": "NEAR-100|80-100|BELOW-80",
  "zygosity_plus_type": "TRANS-CONF-PATH|TRANS-CONF-LIKPATH|TRANS-CONF-VUS|HOM-HEMI",

  // ALT-specific
  "additional_var": {
    "id": "string (optional - hgvs, caid, clinvar, etc.)",
    "classification": "PLP|VUS|BLB",
    "gene": {
      "same_as_VBC": "boolean",
      "associated_with_MDE": "boolean"
    }
  },
  "severity_comparison": "GREATER-THAN-AD|SAME-AS-AD",

  // AFF-specific
  "pheno_spec_gene_type": "SPECIFIC|CONSISTENT|INCONSISTENT",
  "all_rel_disorder_genes_tested": "boolean",
  "vois_exist": "boolean",

  // DNV-specific
  "confirmed_parental": "boolean"
}

Attribute-by-Group Matrix¶

Attribute	General	CLN_UAF	CLN_ALT	CLN_AFF	CLN_DNV
`case_id`	✓	✓	✓	✓	✓
`moi`	✓
`zygosity`	✓
`mde_affected`	✓
`well_phenotyped`	✓
`age_matched_penetrance`		✓
`zygosity_plus_type`		✓ (AR/XLR only)		✓ (AXLR only)
`additional_var.id`			✓
`additional_var.classification`			✓
`additional_var.gene.same_as_VBC`			✓
`additional_var.gene.associated_with_MDE`			✓
`severity_comparison`			✓
`pheno_spec_gene_type`				✓	✓
`all_rel_disorder_genes_tested`				✓	✓
`vois_exist`				✓
`confirmed_parental`					✓

Notes¶

The General attributes are information needed to route a case into the correct CLN group, so they are conceptually present on every case but only explicitly listed in the "General Case" block.
zygosity_plus_type is used in both CLN_UAF (AR/XLR) and CLN_AFF (AXLR) with the combined value set: TRANS-CONF-PATH|TRANS-CONF-LIKPATH|TRANS-CONF-VUS|HOM-HEMI.
CLN_ALT has two sub-types (ALT_Var vs ALT_Gene) distinguished by additional_var.gene.same_as_VBC being true vs false, but they share the same schema.

Reference: Acronyms¶

Core Terms¶

Acronym	Definition
MDE	Mendelian Disease Entity — the disease being assessed as caused by the VBC in an individual
VBC	Variant Being Considered — the target variant being assessed for causality of the MDE
MOI	Mode of Inheritance
CLN	Clinical observations of the VBC in a human (cases where the proband has the VBC)

Mode of Inheritance (MOI) Values¶

Value	Definition
AD	Autosomal Dominant
AR	Autosomal Recessive
SD	Semi Dominant
XLD	X-Linked Dominant
XLR	X-Linked Recessive

MOI Grouping Terms¶

These are not valid moi attribute values. They are shorthand for how specific MOI values are aggregated in the case grouping logic.

Group	Encompasses	Also Known As
AXLD	AD, XLD	Monoallelic
AXLR	AR, XLR, SD	Biallelic
XL	XLD, XLR	X-Linked (either)

CLN Case Groups¶

Group	Definition
CLN_UAF	Unaffected observations — cases where the individual has the VBC but is not affected with the MDE
CLN_ALT	Affected observations with an alternate cause of disease
CLN_AFF	Affected observations (standard — not de novo or alternate cause)
CLN_DNV	Affected observations with de novo variant occurrence (MOI must be AD, SD, XLD, or XLR)

CLN_ALT Sub-Types¶

Sub-Type	Definition
ALT_Var	Affected individual has an additional P/LP variant in the same gene as the VBC
ALT_Gene	Affected individual has an additional P/LP variant in a different gene associated with the same MDE

Attribute Value Abbreviations¶

Value	Definition
PLP	Pathogenic or Likely Pathogenic
VUS	Variant of Uncertain Significance
BLB	Benign or Likely Benign
HOM-HEMI	Homozygous or Hemizygous
TRANS-CONF-PATH	Trans-confirmed Pathogenic
TRANS-CONF-LIKPATH	Trans-confirmed Likely Pathogenic
TRANS-CONF-VUS	Trans-confirmed VUS
DNV	De Novo