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]

Variant: NM_000277.1(PAH):c.673C>G (p.Pro225Ala)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229686

102780 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a087e449-d830-49e4-bceb-5990ab49123a

Approved on: 2021-02-14

Published on: 2021-06-09

HGVS expressions

NM_000277.1:c.673C>G

NM_000277.1(PAH):c.673C>G (p.Pro225Ala)

ENST00000553106.6:c.673C>G

ENST00000307000.7:c.658C>G

ENST00000549111.5:n.769C>G

ENST00000553106.5:c.673C>G

NM_000277.2:c.673C>G

NM_001354304.1:c.673C>G

NM_000277.3:c.673C>G

NM_001354304.2:c.673C>G

NC_000012.12:g.102855169G>C

CM000674.2:g.102855169G>C

NC_000012.11:g.103248947G>C

CM000674.1:g.103248947G>C

NC_000012.10:g.101773077G>C

NG_008690.1:g.67434C>G

NG_008690.2:g.108242C>G

Likely Pathogenic

PP3 PP4_Moderate PM2 PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.673C>G (p.Pro225Ala) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency excluded, PMID: 29499199). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. Another missense change at the same amino acid, p.Pro225Thr, is interpreted as pathogenic by multiple submitters in ClinVar (variation ID 102779). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3.

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster, REVEL=0.986

PP4_Moderate

Detected in a Chinese patient with classic PKU. urinary pterin analysis and a DHPR activity assay were also carried out to distinguish between PAH deficiency and tetrahydrobiopterin deficiency, in addition to sequencing of PAH, PTS, QDPR, GCH1 and PCBD1genes. PMID: 29499199

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PM5

p.P225T pathogenic 2 submitters

Curation History

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