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Table 3 Comparison of PAH enzyme activities reported in a meta-analysis publication Himmelreich et al. [72], the PAH locus-specific database (PAHvdb), and the PAH Variant Curation Expert Panel (VCEP) variant evidence for PS3 criteria

From: Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels

PAH VariantPercentage of enzyme activity by source
cDNAProteinHimmelreich et al. [72] (PMID: 30037505)PAHvdbVCEP evidence for PS3 assertion
Literature ReviewAssay*
c.194T>Cp.(Ile65Thr)26, 27, 33, 48, 60 3325
c.311C>Ap.(Ala104Asp)67772726
c.473G>Ap.(Arg158Gln)2, 5, 9, 10, 29 100.2–1.8
c.533A>Gp.(Glu178Gly)31 3939
c.721C>Tp.(Arg241Cys)25572525
c.754C>Tp.(Arg252Trp)0, 01501
c.755G>Ap.(Arg252Gln)24 33
c.782G>Ap.(Arg261Gln)27, 30, 43, 47, 52234415–30
c.842C>Tp.(Pro281Leu)0, 1, 1 22
c.898G>Tp.(Ala300Ser)32653131
c.916A>Gp.(Ile306Val)12253918
c.926C>Tp.(Ala309Val)70124230
c.1162G>Ap.(Val388Met)15, 23, 43832815
c.1208C>Tp.(Ala403Val)32, 100336643
c.1222C>Tp.(Arg408Trp)0, 1, 3, 5221.3–1.85
c.1223G>Ap.(Arg408Gln)9, 33, 55, 84414646
c.1238G>Cp.(Arg413Pro)21135< 3
c.1241A>Gp.(Tyr414Cys)28, 38, 50, 80 5750
  1. Italicized values indicate measured enzyme activity levels above the > 50% enzyme activity range specified by the VCEP and in direct conflict with the VCEP-cited enzyme activity value in support of PS3 assertion
  2. *Results generated in a PAH enzyme activity assay conducted in Himmelreich et al. [72] (PMID: 30037505). Other results were derived as part of the literature review conducted in Himmelreich et al. [72]
  3. Enzyme activity result generated by PAH expression in E. coli. All other results were generated by PAH expression in COS cells