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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CA16020889

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6b22f5b5-b654-4763-936d-fd132e4d0fbc

Approved on: 2019-07-14

Published on: 2019-07-15

HGVS expressions

NM_000277.3:c.902A>C

NC_000012.12:g.102851697T>G

CM000674.2:g.102851697T>G

NC_000012.11:g.103245475T>G

CM000674.1:g.103245475T>G

NC_000012.10:g.101769605T>G

NG_008690.1:g.70906A>C

NG_008690.2:g.111714A>C

NM_000277.1:c.902A>C

NM_000277.2:c.902A>C

NM_001354304.1:c.902A>C

ENST00000307000.7:c.887A>C

ENST00000549247.6:n.661A>C

ENST00000551114.2:n.564A>C

ENST00000553106.5:c.902A>C

ENST00000635477.1:n.63A>C

Pathogenic

PP4_Moderate PS3 PP3 PM2 PM3_Supporting

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.902A>C (p.Gln301Pro) variant in PAH has been reported in at least 1 individual with hyperphenylalaninemia, who carried a second pathogenic variant (p.Leu48Ser) (BH4 deficiency ruled out, parental analysis not performed) (PMID: 19292873, 25757997) . The p.Gln301Pro variant is absent in gnomAD and the ESP population databases. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.987. In addition the p.Gln301Pro causes a significant reduction of enzyme activity and expression when tested in vitro (PMID: 19292873). In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3_supporting, PS3, PP4_moderate.

PP4_Moderate

Detected in a patient with HPA II. Pre-treatment Phe level 2117 uM. PMID: 19292873 BH4 deficiency excluded. PMID: 25757997

Same patient, Patients with concurrent diseases that would interfere with enrollment or safety, with concomitant drug treatment, with clinical diagnosis of primary BH4 deficiency or unavailable for study participation were excluded from the study. PubMed:25757997

Detected in a patient with HPA II. Pre-treatment Phe level 2117 uM. PubMed:19292873

PS3

Figure 1b demonstrate loss of enzyme activity. 4% residual enzyme activity.

Figure 1b demonstrate loss of enzyme activity: ~4% residual PubMed:19292873

PP3

REVEL 0.987; Polyphen and SIFT damaging

PM2

absent from gnomAD

PM3_Supporting

Detected in trans with pathogenic p.L48S. Parental analysis not reported.

Detected in trans with pathogenic p.L48S (table 2). PubMed:19292873

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