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_000277.2(PAH):c.472C>T (p.Arg158Trp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229570

102693 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: faad1844-5076-4b6f-b671-eeb06035449a

Approved on: 2018-08-10

Published on: 2019-04-06

HGVS expressions

NM_000277.2:c.472C>T

NM_000277.2(PAH):c.472C>T (p.Arg158Trp)

NC_000012.12:g.102866633G>A

CM000674.2:g.102866633G>A

NC_000012.11:g.103260411G>A

CM000674.1:g.103260411G>A

NC_000012.10:g.101784541G>A

NG_008690.1:g.55970C>T

NG_008690.2:g.96778C>T

NM_000277.1:c.472C>T

NM_001354304.1:c.472C>T

NM_000277.3:c.472C>T

ENST00000307000.7:c.457C>T

ENST00000549111.5:n.568C>T

ENST00000551988.5:n.530+10829C>T

ENST00000553106.5:c.472C>T

Pathogenic

PP4_Moderate PS3 PP3 PM2 PM3_Strong

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong).

PP4_Moderate

Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient.

R158W was detected. 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. PubMed:9634518

A novel Arg158 (CGG)-to-Trp158 (TGG) mutation was identified in exon 5 of the PAH gene in a Chinese PKU patient. PubMed:1307609

R158W was observed in the study. PubMed:10429004

PS3

2% mutant enzyme activity in BioPKU

PP3

Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939

PM2

Extremely low frequency. ExAC MAF=0.00019.

PM3_Strong

Detected with 3 pathogenic/likely pathogenic variants

Table 2. Mutant Genotypes. p.R158W: p.R261P (VarID102832, LP). p.R158W: p.R408W (VarID577, Path). p.I65T (VarID:636, P/LP): p.R158W. PubMed:23430918

In case 2, P407S (VarID102568, clinical significance not provided) was detected in one allele and R158W in the other allele. PubMed:14681498

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.