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

CA16020934

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d606fba6-3c95-470e-9df8-21a67044448a

HGVS expressions

NM_000277.1:c.1076C>T

NC_000012.12:g.102843769G>A

CM000674.2:g.102843769G>A

NC_000012.11:g.103237547G>A

CM000674.1:g.103237547G>A

NC_000012.10:g.101761677G>A

NG_008690.1:g.78834C>T

NG_008690.2:g.119642C>T

ENST00000553106.6:c.1076C>T

ENST00000307000.7:c.1061C>T

ENST00000549247.6:n.835C>T

ENST00000551114.2:n.738C>T

ENST00000553106.5:c.1076C>T

ENST00000635477.1:n.180C>T

ENST00000635528.1:n.591C>T

NM_000277.2:c.1076C>T

NM_001354304.1:c.1076C>T

NM_000277.3:c.1076C>T

NM_001354304.2:c.1076C>T

Likely Pathogenic

PM2 PP4_Moderate PM3_Strong PP3

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.1076C>T (p.Ser359Leu) variant in PAH has been reported in multiple individuals with classic PKU (BH4 deficiency excluded). (PMID: 26503515). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.T278I in 2 patients (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_strong, PP3.

PM2

Absent from controls

PP4_Moderate

Seen in 4 individuals 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. PMID: 26503515

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

PM3_Strong

2 patients with p.T278I (P 2 submitters)/p.S359L The validation tests on parents were performed using Sanger sequencing. PMID: 30050108

PP3

Multiple lines of evidence (MutationTaster, SIFT, Polyphen) predict damaging effect.

PM5

No other missense change at this amino acid

Approved on: 2020-06-19

Published on: 2021-09-19

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