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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CA16020837

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 93e7d18e-c7ca-4389-9ecc-cc03c9955c4f

HGVS expressions

NM_000277.1:c.680T>A

ENST00000553106.6:c.680T>A

ENST00000307000.7:c.665T>A

ENST00000549111.5:n.776T>A

ENST00000553106.5:c.680T>A

NM_000277.2:c.680T>A

NM_001354304.1:c.680T>A

NM_000277.3:c.680T>A

NM_001354304.2:c.680T>A

NC_000012.12:g.102855162A>T

CM000674.2:g.102855162A>T

NC_000012.11:g.103248940A>T

CM000674.1:g.103248940A>T

NC_000012.10:g.101773070A>T

NG_008690.1:g.67441T>A

NG_008690.2:g.108249T>A

Likely Pathogenic

PP3 PM3 PM2 PP4_Moderate

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.680T>A (p.Leu227Gln) variant in PAH has been reported in 1 individual with mild PKU (BH4 deficiency excluded, PMID: 26503515, 19915519). This variant is absent in population databases. This variant was detected in trans with pathogenic variant c.611A>G (aka. EX6-96A>G, PMID:30050108). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.971.

PM3

Detected with p.EX6-96A>G. The validation tests on parents were performed using Sanger sequencing. PMID: 30050108

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

Reported in Chinese PKU patients. BH4 deficiency was assessed by dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading PMID: 26503515, PMID: 19915519

A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. L227Q was seen on 2 alleles. PubMed:26503515

212 unrelated Chinese Han patients with PKU were investigated. L227Q was seen with relative frequency 0.0025%. PubMed:19915519

Approved on: 2020-08-07

Published on: 2021-09-26

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