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]

Link to SEPIO compliant JSON-LD document

CA16020914

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 58755e24-21d1-4931-abea-5a6aac56443d

HGVS expressions

NM_000277.1:c.983C>A

ENST00000553106.6:c.983C>A

ENST00000307000.7:c.968C>A

ENST00000549247.6:n.742C>A

ENST00000551114.2:n.645C>A

ENST00000553106.5:c.983C>A

ENST00000635477.1:n.87C>A

ENST00000635528.1:n.498C>A

NM_000277.2:c.983C>A

NM_001354304.1:c.983C>A

NM_000277.3:c.983C>A

NM_001354304.2:c.983C>A

NC_000012.12:g.102844418G>T

CM000674.2:g.102844418G>T

NC_000012.11:g.103238196G>T

CM000674.1:g.103238196G>T

NC_000012.10:g.101762326G>T

NG_008690.1:g.78185C>A

NG_008690.2:g.118993C>A

Uncertain Significance

PM2 PP3 PP4_Moderate

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.983C>A (p.Thr328Asn) variant in PAH has been reported in a Chinese patient with PAH deficiency (BH4 deficiency excluded, PMID: 26503515). This variant is absent in 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.

PM2

Absent from 1000G, ESP, ExAC, gnomAD

PP3

predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.91

PP4_Moderate

T328N seen on 1 PKU allele. BH4 deficiency was assessed by dihydropteridine reductase activity, urinary biopterin and neopterin ratio. PMID: 26503515

A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. These patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Demographic data and biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. T328N was seen on 1 allele. PubMed:26503515

PM5

T328A, no clinical significance; T328I, VUS

Approved on: 2020-08-10

Published on: 2021-09-26

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