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]

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CA16020854

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c746efb0-6516-407e-bad0-a2cc5b62fb0b

HGVS expressions

NM_000277.1:c.755G>C

NM_000277.2:c.755G>C

NM_001354304.1:c.755G>C

NM_000277.3:c.755G>C

NM_001354304.2:c.755G>C

ENST00000307000.7:c.740G>C

ENST00000549247.6:n.514G>C

ENST00000553106.5:c.755G>C

NC_000012.12:g.102852902C>G

CM000674.2:g.102852902C>G

NC_000012.11:g.103246680C>G

CM000674.1:g.103246680C>G

NC_000012.10:g.101770810C>G

NG_008690.1:g.69701G>C

NG_008690.2:g.110509G>C

Likely Pathogenic

PP3 PM2 PM5 PM3 PP4_Moderate

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.755G>C (p.Arg252Pro) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded, PMID: 21307867). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.Arg243Gln (PMID: 29316886). Computational evidence supports a deleterious effect. Other missense variants at the p.Arg252 amino acid are pathogenic (p.Arg252Gln/Trp/Gly). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PM5, PP3.

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.966

PM2

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

PM5

p.Arg252Gln/Trp/Gly pathogenic

PM3

Detected in trans with p.Arg243Gln (P 10 submitters) variable sites in patient genes were aligned with the corresponding sites from the respective parents. PMID: 29316886

PubMed:29316886

PP4_Moderate

PMID 21307867: 5 alleles of p.Arg252Pro in a cohort of Japanese PKU patients. Serum phenylalanine level higher than 0.18mM. analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine.

In Table 2, listed 5 alleles of p.Arg252Pro in a cohort of Japanese PKU patients. PubMed:21307867

Approved on: 2020-03-15

Published on: 2020-03-15

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