Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000277.1(PAH):c.754C>G (p.Arg252Gly)

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CA229742

102823 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1e25ace3-fb0d-46cc-a64d-e393e6780847

Approved on: 2018-12-08

Published on: 2019-08-17

HGVS expressions

NM_000277.1:c.754C>G

NM_000277.1(PAH):c.754C>G (p.Arg252Gly)

NC_000012.12:g.102852903G>C

CM000674.2:g.102852903G>C

NC_000012.11:g.103246681G>C

CM000674.1:g.103246681G>C

NC_000012.10:g.101770811G>C

NG_008690.1:g.69700C>G

NG_008690.2:g.110508C>G

NM_000277.2:c.754C>G

NM_001354304.1:c.754C>G

NM_000277.3:c.754C>G

ENST00000307000.7:c.739C>G

ENST00000549247.6:n.513C>G

ENST00000553106.5:c.754C>G

Pathogenic

PP4_Moderate PM2 PS3 PM5 PP3

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.754C>G (p.Arg252Gly) variant in PAH has been reported in multiple individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 1363786, 9634518). This variant is absent in population databases (PM2). This variant has 3% enzyme activity (PS3; PMID: 9799096). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). This missense change is at an amino acid residue where different pathogenic missense changes have been seen before (p.Arg252Gln/Trp). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM5, PP3.

PP4_Moderate

Detected in a patient with classic PKU. BH4 deficiency was excuded. PMID: 1363786, 9634518

In all patients, hyperphenylalaninemia had been detected by national mass screening programs, and PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism. R252G was detected in a patient with classic PKU. PubMed:9634518

Quote abstract "Complete sequence analysis of 194 human phenylalanine hydroxylase genes from PKU patients originating from West Germany and Bulgaria revealed 13 different mutations within exon 7 of the gene. Four of these mutations (T238P: ACT-->CCT; L242F:CTC-->TTC; R252G:CGG-->GGG; and 1043 delta 11: nt 1043-nt 1053 deleted) have so far not been described in the literature." PubMed:1363786

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, or ESP

PS3

5.2% enzyme activity PMID: 9799096

R252G revealed a residual activity of 5.2% (Table 2). PubMed:9799096

PM5

p.Arg252Gln/Trp pathogenic (VarID 102824, 584)

PP3

Multiple lines of computational evidence support a deleterious effect: SIFT (D), PolyPhen2 (D), MutationTaster (D), REVEL=0.951.

Curation History

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