Table 1 Overview of Variant Curation Expert Panel (VCEP) disease areas and mechanisms, functional assay classes, and accompanying strength level modifications
From: Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels
VCEP | Gene | MONDO ID for disease | Molecular etiology | Inheritance pattern | GO term for disease mechanism-related function/localization | Class of assay | Max evidence level | |
|---|---|---|---|---|---|---|---|---|
PS3 | BS3 | |||||||
CDH1 | CDH1 | MONDO:0007648 (hereditary diffuse gastric adenocarcinoma) | LOF | AD | Splicing assessment | S | S | |
GO:0098641 (cadherin binding involved in cell-cell adhesion) | Cell aggregation assay | Not approved | ||||||
GO:0030336 (negative regulation of cell migration) | Cell invasion assay | Not approved | ||||||
Wound closure assay | Not approved | |||||||
GO:0016342 (catenin complex) | Proximity ligation assay | Not approved | ||||||
Hearing Loss | COCH | MONDO:0011058 (DFNA9) | GOF/DN | AD | GO:0032940 (secretion by cell) | Secretion assay | M | P |
GO:0005615 (localization in extracellular space) | Localization assay | M | P | |||||
Dimerization assay | M | P | ||||||
GJB2 | MONDO:0009076 (DFNB1) MONDO:0011103 (DFNA3A) | DFNB1: LOF DFNA3A: DN | DFNB1: AR DFNA3A: AD | GO:0005243 (gap junction channel activity) | Electrical coupling assay | M | P | |
GO:0007267 (cell-cell signaling) | Dye diffusion assay | M | P | |||||
SLC26A4 | MONDO:0010933 (DFNB4) | LOF | AR | GO:0006811 (ion transport) | Radioactive anion isotope transport assay | P | P | |
GO:0006885 (regulation of pH) | Fluorescent anion transport assay | P | P | |||||
All genes | MONDO:0019497 (nonsyndromic genetic deafness) | Varies | Varies | Mouse knock-in model | S | |||
Other functional assays with limited validation | P | |||||||
Inherited cardiomyopathy | MYH7 | MONDO:0024573 (familial hypertrophic cardiomyopathy) MONDO:0005021 (dilated cardiomyopathy) MONDO:0005201 (restrictive cardiomyopathy) | GOF | AD | GO:0060048 (cardiac muscle contraction) | Mammalian knock-in model | S | |
GO:0000146 (microfilament motor activity) | Motility assay | Not approved | ||||||
GO:0051117 (ATPase binding) | ATPase assay | Not approved | ||||||
PAH | PAH | MONDO: 0009861 (phenylketonuria) | LOF | AR | GO:0004505 (phenylalanine 4-monooxygenase activity) | PAH enzyme activity assay | S | S |
PTEN | PTEN | MONDO:0017623 (hamartoma tumor syndrome) | LOF | AD | GO:0046856 (phosphatidylinositol dephosphorylation) | Phosphatase activity assay | S | S* |
Splicing assessment | S | S | ||||||
PTEN/pAKT expression assay | P | |||||||
GO:0005634 (localization in nucleus) | Localization assay | P | ||||||
GO:0030336 (negative regulation of cell migration) | Cell migration/invasion assay | P | ||||||
GO:0042127 (regulation of cell proliferation) | Cell proliferation assay | P | ||||||
Transgenic model organism | P | |||||||
RASopathy | BRAF | MONDO:0015280 (cardio-acio-cutaneous syndrome) | GOF | AD | GO:0000186 (activation of MAPKK activity) | MAP 2 K1/2 and ERK1/2 phosphorylation assay | S | S |
GO:0004674 (protein serine/threonine kinase activity) | BRAF kinase activity assay | S | S | |||||
GO:0009887 (animal organ morphogenesis) | Mouse or zebrafish model | S | S | |||||
HRAS | MONDO:0009026 (Costello syndrome) | GOF | AD | GO:0043410 (positive regulation of MAPK cascade) | MAP2K1/2 and ERK1/2 phosphorylation assay | S | S | |
GO:0005525 (GTP binding) | RAF1 or RBD binding assay | S | S | |||||
GO:0009887 (animal organ morphogenesis) | Mouse or zebrafish model | S | S | |||||
KRAS | MONDO:0015280 (cardio-facio-cutaneous syndrome) | GOF | AD | GO:0043406 (positive regulation of MAP kinase activity) | MAP2K1/2 and ERK1/2 phosphorylation assay | S | S | |
MAP 2 K1/2 | MONDO:0015280 (cardio-facio-cutaneous syndrome) | GOF | AD | GO:0004708 (MAP kinase kinase activity) | ERK1/2 phosphorylation assay | S | S | |
PTPN11 | MONDO:0018997 (Noonan syndrome) | GOF | AD | GO:0004725 (protein tyrosine phosphatase activity) | SHP-2 phosphatase activity assay | S | S | |
GO:0000187 (activation of MAPK activity) | ERK1/2 activation assay | S | S | |||||
GO:0009887 (animal organ morphogenesis) | Mouse, zebrafish, or Drosophila model | S | S | |||||
RAF1 | MONDO:0018997 (Noonan syndrome) | GOF | AD | GO:0000186 (activation of MAPKK activity) | MAP2K1/2 and ERK1/2 phosphorylation assay | S | S | |
GO:0004674 (protein serine/threonine kinase activity) | RAF1 kinase activity assay | S | S | |||||
GO:0009887 (animal organ morphogenesis) | Mouse model | S | S | |||||
SHOC2 | MONDO:0018997 (Noonan syndrome) | GOF | AD | GO:0005634 (localization in nucleus) | Myristoylation assay | S | S | |
SOS1 | MONDO:0018997 (Noonan syndrome) | GOF | AD | GO:0005088 (Ras guanyl-nucleotide exchange factor activity) | RAS activation assay | S | S | |
GO:0007265 (Ras protein signal transduction) | ERK1/2 activation assay | S | S | |||||
GO:0009887 (animal organ morphogenesis) | Mouse model | S | S | |||||