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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CA16020725

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: eb8fc60b-294f-467e-a1fc-fafa252aea80

Approved on: 2019-11-22

Published on: 2020-01-25

HGVS expressions

NM_000277.3:c.61-3T>C

NC_000012.12:g.102912901A>G

CM000674.2:g.102912901A>G

NC_000012.11:g.103306679A>G

CM000674.1:g.103306679A>G

NC_000012.10:g.101830809A>G

NG_008690.1:g.9702T>C

NG_008690.2:g.50510T>C

NM_000277.1:c.61-3T>C

NM_000277.2:c.61-3T>C

NM_001354304.1:c.61-3T>C

ENST00000307000.7:c.46-3T>C

ENST00000546844.1:c.61-3T>C

ENST00000548677.2:n.148-3T>C

ENST00000549111.5:n.157-3T>C

ENST00000550978.6:n.45-3T>C

ENST00000551337.5:c.61-3T>C

ENST00000551988.5:n.150-3T>C

ENST00000553106.5:c.61-3T>C

ENST00000635500.1:n.29-3T>C

Uncertain Significance

PM2 PM3 BP4 PP4_Moderate

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.61-3T>C variant in PAH was reported twice in the Chinese PKU population, although this may be the same patient (PMID: 26503515; 28982351). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is absent from the population databases ExAC and gnomAD. However, in silico splicing predictions suggest no splicing impact (HSP, MaxENT, TraP). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2, PM3, BP4.

PM2

Absent from population databases gnomAD and ExAC.

PM3

This variant was detected in trans with the pathogenic PAH variant Arg111Ter in 1 patient with classic PKU (Phe > 1200 µmol/L) (PMID: 28982351).

This variant was detected in trans with the pathogenic PAH variant Arg111Ter in 1 patient with classic PKU (Phe > 1200 µmol/L). Parental analysis was performed to confirm compound heterozygosity (PMID: 28982351). PubMed:28982351

BP4

According to in silico splicing predictions, no significant splicing motif alteration was detected and this mutation probably has no impact on splicing (Human Splicing Finder). This alteration is considered probably benign (TraP score 0.175).

PP4_Moderate

This variant was reported once in a Northern Chinese patient with PAH deficiency (PMID: 26503515).

This variant was reported once in a Northern Chinese patient with PAH deficiency (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. PubMed:26503515

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