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_000277.3(PAH):c.205C>T (p.Pro69Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229486

102628 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9370fcab-fbf4-4a22-a254-33daee7a31c0

Approved on: 2023-03-16

Published on: 2023-03-16

HGVS expressions

NM_000277.3:c.205C>T

NM_000277.3(PAH):c.205C>T (p.Pro69Ser)

NC_000012.12:g.102894882G>A

CM000674.2:g.102894882G>A

NC_000012.11:g.103288660G>A

CM000674.1:g.103288660G>A

NC_000012.10:g.101812790G>A

NG_008690.1:g.27721C>T

NG_008690.2:g.68529C>T

ENST00000553106.6:c.205C>T

ENST00000307000.7:c.190C>T

ENST00000546844.1:c.205C>T

ENST00000548677.2:n.292C>T

ENST00000548928.1:n.127C>T

ENST00000549111.5:n.301C>T

ENST00000550978.6:n.189C>T

ENST00000551337.5:c.205C>T

ENST00000551988.5:n.294C>T

ENST00000553106.5:c.205C>T

ENST00000635500.1:n.173C>T

NM_000277.1:c.205C>T

NM_000277.2:c.205C>T

NM_001354304.1:c.205C>T

NM_001354304.2:c.205C>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PP4_Moderate PM2 PM3

PS3 PS1 PP3 PM1 PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.205C>T (p.Pro69Ser) variant in PAH has been reported in at least two individuals with PKU without specified Phe levels, including at least one for whom BH4 deficiency has been excluded (PMID: 15503242, PMID: 32668217, PMID: 26503515). p.Pro69Ser has been detected at least twice with p.Arg261Gln, which is classified pathogenic by PAH VCEP, but without documentation of parental testing to establish phase. In-vitro studies show reduced enzyme activity, but not below the PAH VCEP cutoff of 50% (PMID: 16253218). p.Pro69Ser is absent from population databases. Multiple lines of computational evidence yield inconsistent predictions regarding the impact of this substitution. In summary, this variant meets criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3.

PP4_Moderate

Observed with PAH deficiency with BH4 deficiency excluded, but without a documented Phe level and without a known PKU type (PMID: 15503242, PMID: 26503515).

PM2

Absent from 1000G, ESP, gnomAD

PM3

P69S observed at least twice with R261Q, which is pathogenic according to PAH VCEP (ID 582)

PS3

Kim et al. 2006 PMID: 16253218 – in-vitro expression analysis showed mean enzyme activity 52% of wild-type (PS3 not met)

PS1

No additional variants at this codon in ClinVar.

PP3

Computational predictions yield inconsistent results (predicted tolerated in SIFT, possibly damaging in Polyphen2, disease-causing in MutationTaster, REVEL = 0.673).

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

No additional variants at this codon in ClinVar.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.