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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CA6748732

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b0f1905b-b918-4f3d-95b4-0ffeb33d2386

HGVS expressions

NM_000277.3:c.1174T>A

NC_000012.12:g.102843671A>T

CM000674.2:g.102843671A>T

NC_000012.11:g.103237449A>T

CM000674.1:g.103237449A>T

NC_000012.10:g.101761579A>T

NG_008690.1:g.78932T>A

NG_008690.2:g.119740T>A

NM_000277.1:c.1174T>A

NM_000277.2:c.1174T>A

NM_001354304.1:c.1174T>A

ENST00000307000.7:c.1159T>A

ENST00000549247.6:n.933T>A

ENST00000551114.2:n.836T>A

ENST00000553106.5:c.1174T>A

ENST00000635477.1:n.278T>A

ENST00000635528.1:n.689T>A

Pathogenic

PM3_Very Strong PP3 PP4_Moderate

PM2

Evidence Links 8

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1174T>A (p.F392I) variant was documented 19 times in patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 26503515, 30459323, 26322415, 30747360). This variant was detected in at least 8 mild hyperphenylalaninemia (MHP) patients and 1 classical PKU patient with a pathogenic variant in trans (PMID: 24401910, 29316886, 30050108, 31445982). This missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease causing (MutationTaster). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM3_very strong.

PM3_Very Strong

This variant was detected in at least 8 mild hyperphenylalaninemia (MHP) patients and 1 classical PKU patient with a pathogenic variant in trans (PMID: 24401910, 29316886, 30050108, 31445982).

This variant was detected in trans with the pathogenic PAH variant Arg408Gln in 1 patient with mild hyperphenylalaninemia. Parental analysis was not performed to confirm compound heterozygosity. This variant was documented in a 2nd patient diagnosed with mild hyperphenylalaninemia (MHP), however, the variant in trans was not specified. PubMed:24401910

This variant was documented in one patient with mild hyperphenylalaninemia with the pathogenic variant c.331C>T (p.Arg111Ter) in trans. Parental analysis was not performed to confirm compound heterozygosity. PubMed:31445982

This variant was documented in 7 Chinese patients diagnosed with mild hyperphenylalaninemia. The reported variant in trans for each of the patients was the pathogenic variant c.1197A>T (in 2 patients), the pathogenic variant c.728G>A (p.Arg243Gln) (in 1 patient), the pathogenic variant c.721C>T (in 1 patient), the VUS c.1099C>G (in 1 patient), c.763T>G (in 1 patient), and c.460T>C (in 1 patient). Parental analysis was performed to confirm compound heterozygosity. PubMed:30050108

This variant was detected in trans with the pathogenic variant p.Tyr356* in 2 patients, one was diagnosed with mild hyperphenylalaninemia and the 2nd was diagnosed with classic PKU. This variant was detected in trans with the pathogenic variant p.Arg243Gln in a patient diagnosed with mild hyperphenylalaninemia. This variant was detected in trans with the pathogenic variant p.Ser70del in a patient diagnosed with mild hyperphenylalaninemia. This variant was detected in a second patient diagnosed with classical PKU, however the variant in trans was not reported. Parental analysis was performed to confirm compound heterozygosity. PubMed:29316886

PP3

Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster)

PP4_Moderate

This variant was documented 19 times in patients with PAH deficiency (PMID: 26503515, 30459323, 26322415, 30747360).

This variant was documented 5 times in patients diagnosed with mild hyperphenylalaninemia (MHP) in Northwest China. It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant. PubMed:30747360

This variant was documented 7 times in mild hyperphenylalaninemia (Phe value of <360 µmol/L) patients from Zhejiang Province. It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant. PubMed:30459323

This variant was documented in trans with the VUS p.L367V in 1 patient diagnosed with mild hyperphenylalaninemia. PubMed:26322415

This variant was documented three times in Southern Chinese patients and three times in Northern Chinese patients with PAH deficiency (PMID: 26503515). It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant. Subjects in this study were diagnosed through neonatal screening program or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. PubMed:26503515

PM2

Present in East Asian populations at frequency of 0.00198 and in all populations at frequency of 0.00040 (1000 Genomes). The PM2 threshold set by the PAH Variant Curation Expert Panel (VCEP) is 0.0002.

Approved on: 2019-10-17

Published on: 2019-10-18

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