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

CA16020942

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 109a434d-9d5c-49f8-9e98-7216865f07d6

HGVS expressions

NM_000277.3:c.1115C>G

ENST00000553106.6:c.1115C>G

ENST00000307000.7:c.1100C>G

ENST00000549247.6:n.874C>G

ENST00000551114.2:n.777C>G

ENST00000553106.5:c.1115C>G

ENST00000635477.1:n.219C>G

ENST00000635528.1:n.630C>G

NM_000277.1:c.1115C>G

NM_000277.2:c.1115C>G

NM_001354304.1:c.1115C>G

NM_001354304.2:c.1115C>G

NC_000012.12:g.102843730G>C

CM000674.2:g.102843730G>C

NC_000012.11:g.103237508G>C

CM000674.1:g.103237508G>C

NC_000012.10:g.101761638G>C

NG_008690.1:g.78873C>G

NG_008690.2:g.119681C>G

Likely Pathogenic

PM3_Strong PP3 PM2 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.1115C>G (p.Thr372Arg) variant in PAH has been reported in 3 individuals with classic PKU (BH4 deficiency excluded, PMID: 26503515) detected in trans with pathogenic variants: p.R176* (2 patients) and p.R408W (PMID: 30050108). This variant is absent in population databases. Computational evidence support 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_strong, PP3.

PM3_Strong

Detected in trans with p.R176* (2 patients, P 9 submitters), and p.R408W (P 17 submitters). The validation tests on parents were performed using Sanger sequencing. PMID: 30050108

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.922

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

T372R was found in 3 patients with classic PKU. BH4 deficiency was assessed by dihydropteridine reductase activity, urinary biopterin and neopterin ratio PMID: 26503515, PMID: 30050108

PAH mutations complied from 796 PKU patients from mainland China. Demographic data and biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.T372R was found on 2 alleles. PubMed:26503515

PM5

T372S is Likely Pathogenic 2 submitters

Approved on: 2020-08-10

Published on: 2021-09-26

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