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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CA6748709

619167 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 99c1aff1-c37d-4471-90f9-86d122e11e34

HGVS expressions

NM_000277.1:c.1216A>G

NC_000012.12:g.102840499T>C

CM000674.2:g.102840499T>C

NC_000012.11:g.103234277T>C

CM000674.1:g.103234277T>C

NC_000012.10:g.101758407T>C

NG_008690.1:g.82104A>G

NG_008690.2:g.122912A>G

NM_000277.2:c.1216A>G

NM_001354304.1:c.1216A>G

NM_000277.3:c.1216A>G

ENST00000307000.7:c.1201A>G

ENST00000551114.2:n.878A>G

ENST00000553106.5:c.1216A>G

ENST00000635477.1:n.320A>G

ENST00000635528.1:n.731A>G

Likely Pathogenic

PM5 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

The c.1216A>G (p.Ile406Val) variant in PAH is reported in an individual with PKU. Dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading were collected. (PMID: 26503515) This variant has a low frequency in ExAC/gnomAD (MAF=0.00016) and is absent from 1000G. A deleterious effect is predicted by SIFT, Polyphen, and MutationTaster. Another missense variant at this amino acid is interpreted as likely pathogenic by our PAH VCEP (p.I406T). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP4_Moderate, PP3.

PM5

I406T curated as likely pathogenic

PM2

Low AF in ExAC/gnomAD: (MAF:0.00016) and absent from 1000G.

PP4_Moderate

Seen in an individual with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PMID: 26503515.

Seen in an individual with PKU. These patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PubMed:26503515

PP3

Support a deleterious effect: deleterious by SIFt, possibly damaging by Polyphen, and damaging by MutationTaster

Approved on: 2018-12-09

Published on: 2019-04-06

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