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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Variant: NM_000277.1(PAH):c.981T>G (p.Phe327Leu)

CA229889

102922 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 351a13b0-fdac-4699-b0d6-94e29cdc99b8

HGVS expressions

NM_000277.1:c.981T>G

NM_000277.1(PAH):c.981T>G (p.Phe327Leu)

NC_000012.12:g.102844420A>C

CM000674.2:g.102844420A>C

NC_000012.11:g.103238198A>C

CM000674.1:g.103238198A>C

NC_000012.10:g.101762328A>C

NG_008690.1:g.78183T>G

NG_008690.2:g.118991T>G

NM_000277.2:c.981T>G

NM_001354304.1:c.981T>G

NM_000277.3:c.981T>G

NM_001354304.2:c.981T>G

ENST00000307000.7:c.966T>G

ENST00000549247.6:n.740T>G

ENST00000551114.2:n.643T>G

ENST00000553106.5:c.981T>G

ENST00000635477.1:n.85T>G

ENST00000635528.1:n.496T>G

Uncertain Significance

PP3 PM2 PP4_Moderate

PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.981T>G (p.Phe327Leu) variant in PAH has been reported in a German patient with classic PKU (BH4 deficiency excluded) (PMID: 9634518, 10394930) This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3.

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster, REVEL=0.95

PM2

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

PP4_Moderate

PMID 9634518 classified it as classic PKU variant. PMID 10394930: Table 1 listed it in one patient (Phe level not specified). PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism (Scriver et al. 1995)

PMID 10394930: Patients with PAH-deficient hyperphenylalaninaemia in 272 independent families (248 PKU and 24 MHP) living in Germany were investigated. Table 1 listed it in one patient (Phe level not specified). PubMed:10394930

PMID 9634518 classified it as classic PKU variant. PubMed:9634518

PM5

The current variant is the only variant found in this codon in ClinVar.

Approved on: 2020-04-03

Published on: 2020-04-03

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