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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

VCEPGeneMONDO ID for diseaseMolecular etiologyInheritance patternGO term for disease mechanism-related function/localizationClass of assayMax evidence level
PS3BS3
CDH1CDH1MONDO:0007648 (hereditary diffuse gastric adenocarcinoma)LOFAD Splicing assessmentSS
GO:0098641 (cadherin binding involved in cell-cell adhesion)Cell aggregation assayNot approved
GO:0030336 (negative regulation of cell migration)Cell invasion assayNot approved
Wound closure assayNot approved
GO:0016342 (catenin complex)Proximity ligation assayNot approved
Hearing LossCOCHMONDO:0011058 (DFNA9)GOF/DNADGO:0032940 (secretion by cell)Secretion assayMP
GO:0005615 (localization in extracellular space)Localization assayMP
 Dimerization assayMP
GJB2MONDO:0009076 (DFNB1)
MONDO:0011103 (DFNA3A)
DFNB1: LOF
DFNA3A: DN
DFNB1: AR
DFNA3A: AD
GO:0005243 (gap junction channel activity)Electrical coupling assayMP
GO:0007267 (cell-cell signaling)Dye diffusion assayMP
SLC26A4MONDO:0010933 (DFNB4)LOFARGO:0006811 (ion transport)Radioactive anion isotope transport assayPP
GO:0006885 (regulation of pH)Fluorescent anion transport assayPP
All genesMONDO:0019497 (nonsyndromic genetic deafness)VariesVaries Mouse knock-in modelS 
 Other functional assays with limited validationP 
Inherited cardiomyopathyMYH7MONDO:0024573 (familial hypertrophic cardiomyopathy)
MONDO:0005021 (dilated cardiomyopathy)
MONDO:0005201 (restrictive cardiomyopathy)
GOFADGO:0060048 (cardiac muscle contraction)Mammalian knock-in modelS 
GO:0000146 (microfilament motor activity)Motility assayNot approved
GO:0051117 (ATPase binding)ATPase assayNot approved
PAHPAHMONDO: 0009861 (phenylketonuria)LOFARGO:0004505 (phenylalanine 4-monooxygenase activity)PAH enzyme activity assaySS
PTENPTENMONDO:0017623 (hamartoma tumor syndrome)LOFADGO:0046856 (phosphatidylinositol dephosphorylation)Phosphatase activity assaySS*
 Splicing assessmentSS
 PTEN/pAKT expression assayP 
GO:0005634 (localization in nucleus)Localization assayP 
GO:0030336 (negative regulation of cell migration)Cell migration/invasion assayP 
GO:0042127 (regulation of cell proliferation)Cell proliferation assayP 
 Transgenic model organismP 
RASopathyBRAFMONDO:0015280 (cardio-acio-cutaneous syndrome)GOFADGO:0000186 (activation of MAPKK activity)MAP 2 K1/2 and ERK1/2 phosphorylation assaySS
GO:0004674 (protein serine/threonine kinase activity)BRAF kinase activity assaySS
GO:0009887 (animal organ morphogenesis)Mouse or zebrafish modelSS
HRASMONDO:0009026 (Costello syndrome)GOFADGO:0043410 (positive regulation of MAPK cascade)MAP2K1/2 and ERK1/2 phosphorylation assaySS
GO:0005525 (GTP binding)RAF1 or RBD binding assaySS
GO:0009887 (animal organ morphogenesis)Mouse or zebrafish modelSS
KRASMONDO:0015280 (cardio-facio-cutaneous syndrome)GOFADGO:0043406 (positive regulation of MAP kinase activity)MAP2K1/2 and ERK1/2 phosphorylation assaySS
MAP 2 K1/2MONDO:0015280 (cardio-facio-cutaneous syndrome)GOFADGO:0004708 (MAP kinase kinase activity)ERK1/2 phosphorylation assaySS
PTPN11MONDO:0018997 (Noonan syndrome)GOFADGO:0004725 (protein tyrosine phosphatase activity)SHP-2 phosphatase activity assaySS
GO:0000187 (activation of MAPK activity)ERK1/2 activation assaySS
GO:0009887 (animal organ morphogenesis)Mouse, zebrafish, or Drosophila modelSS
RAF1MONDO:0018997 (Noonan syndrome)GOFADGO:0000186 (activation of MAPKK activity)MAP2K1/2 and ERK1/2 phosphorylation assaySS
GO:0004674 (protein serine/threonine kinase activity)RAF1 kinase activity assaySS
GO:0009887 (animal organ morphogenesis)Mouse modelSS
SHOC2MONDO:0018997 (Noonan syndrome)GOFADGO:0005634 (localization in nucleus)Myristoylation assaySS
SOS1MONDO:0018997 (Noonan syndrome)GOFADGO:0005088 (Ras guanyl-nucleotide exchange factor activity)RAS activation assaySS
GO:0007265 (Ras protein signal transduction)ERK1/2 activation assaySS
GO:0009887 (animal organ morphogenesis)Mouse modelSS
  1. Evidence strength level modifications of PS3 or BS3 evidence abbreviated as “S” for strong, “M” for moderate, and “P” for supporting, see Additional file 1 for supporting information and references
  2. AD autosomal dominant, AR autosomal recessive, DN dominant negative, GOF gain-of-function, LOF loss-of-function
  3. *Must be accompanied by a second assay demonstrating no statistically significant difference from wild type to be used as evidence for BS3 application
  4. Italicized assays represent classes of assays not approved by the VCEP