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

CA16020931

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5b55acd3-9614-486c-a9bb-19b5225f1e82

HGVS expressions

NM_000277.3:c.1066T>G

NC_000012.12:g.102843779A>C

CM000674.2:g.102843779A>C

NC_000012.11:g.103237557A>C

CM000674.1:g.103237557A>C

NC_000012.10:g.101761687A>C

NG_008690.1:g.78824T>G

NG_008690.2:g.119632T>G

NM_000277.1:c.1066T>G

NM_000277.2:c.1066T>G

NM_001354304.1:c.1066T>G

ENST00000307000.7:c.1051T>G

ENST00000549247.6:n.825T>G

ENST00000551114.2:n.728T>G

ENST00000553106.5:c.1066T>G

ENST00000635477.1:n.170T>G

ENST00000635528.1:n.581T>G

Uncertain Significance

PM2 PP4_Moderate PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1066T>G (p.Y356D) variant in PAH was reported in 1 Southern Chinese patient with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is present in African American populations at a frequency of 0.00003 and Native Hawaiian populations at a frequency of 0.00022 (PAGE). In silico modeling predicts that this missense variant is damaging (SIFT), probably damaging (PolyPhen2), and disease causing (mutation taster). In summary, this variant meets criteria to be classified as Uncertain Significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4, PP3.

PM2

Absent from population databases gnomAD and ExAC. Present in Native Hawaiian populations at a frequency of 0.00022 (PAGE).

PP4_Moderate

This variant was documented in 1 Southern Chinese patient (PMID: 26503515). The patient was a compound heterozygote for the variant, however the 2nd allele was not specified. Subjects in this study were diagnosed through neonatal screening program or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay.

PP3

Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (mutation taster).

Approved on: 2019-11-05

Published on: 2019-11-06

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.