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_000277.2(PAH):c.823C>T (p.Pro275Ser)

Curation Version - 1.0
Curation History
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CA229789

102853 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 85ea4e16-15ba-4de1-88b7-46e398122a6e

Approved on: 2018-12-09

Published on: 2019-04-05

HGVS expressions

NM_000277.2:c.823C>T

NM_000277.2(PAH):c.823C>T (p.Pro275Ser)

NC_000012.12:g.102852834G>A

CM000674.2:g.102852834G>A

NC_000012.11:g.103246612G>A

CM000674.1:g.103246612G>A

NC_000012.10:g.101770742G>A

NG_008690.1:g.69769C>T

NG_008690.2:g.110577C>T

NM_000277.1:c.823C>T

NM_001354304.1:c.823C>T

NM_000277.3:c.823C>T

ENST00000307000.7:c.808C>T

ENST00000549247.6:n.582C>T

ENST00000553106.5:c.823C>T

Pathogenic

PP4_Moderate PM2 PM5 PP3 PM3_Strong

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.823C>T (p.Pro275Ser) variant in PAH is absent from all population databases, and is in the same codon as two other likely pathogenic variants. In silico algorithms agree on a damaging effect. It has been identified in trans with two independent pathogenic variants (R408W and c.669delC; PMID: 20123475, 24705691), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in multiple patients. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PM5, PP3.

PP4_Moderate

BH4 defect excluded in all patients (PMID: 24705691, PMID: 20123475). Phe = 380umol/L (Gassio 2010)

BH4 defect excluded in all patients PubMed:24705691

BH4 defect excluded in all patients PubMed:20123475

PM2

not found in any population databases

PM5

p.Pro275Leu and p.Pro275Arg, both LP in ClinVar

PP3

In silico agree damaging. REVEL=0.954

PM3_Strong

R408W (Cassio, 2010) c.669delC (Gu, 2014)

in trans with c.669delC PubMed:24705691

in trans with R408W PubMed:20123475

Curation History

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