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.940C>T (p.Pro314Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229865

102905 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bd417e52-1ddf-48db-8a18-b1341bfa724a

Approved on: 2018-12-09

Published on: 2019-04-06

HGVS expressions

NM_000277.2:c.940C>T

NM_000277.2(PAH):c.940C>T (p.Pro314Ser)

NC_000012.12:g.102846924G>A

CM000674.2:g.102846924G>A

NC_000012.11:g.103240702G>A

CM000674.1:g.103240702G>A

NC_000012.10:g.101764832G>A

NG_008690.1:g.75679C>T

NG_008690.2:g.116487C>T

NM_000277.1:c.940C>T

NM_001354304.1:c.940C>T

NM_000277.3:c.940C>T

ENST00000307000.7:c.925C>T

ENST00000549247.6:n.699C>T

ENST00000551114.2:n.602C>T

ENST00000553106.5:c.940C>T

ENST00000635477.1:n.74-2493C>T

ENST00000635528.1:n.455C>T

Pathogenic

PS3 PP4_Moderate PM2 PM3 PM5

PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.940C>T (p.Pro314Ser) variant in PAH is absent in population databases, and is in the same codon as two previously described Pathogenic/Likely pathogenic variants (p.Pro314His and p.Pro314Thr). It has been found in trans with a pathogenic variant (p.R408W) in a patient with PAH deficiency (BH4 defects excluded, PMID: 12501224). Functional studies showed it has 26% enzyme activity compared to wild type controls. PMID: 18590700. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3, PM5.

PS3

26% enzyme activity. PMID: 18590700

PP4_Moderate

BH4 defect excluded in all patients. PMID: 12501224

PM2

Not identified in any population databases

PM3

in trans with p.R408W

PM5

p.Pro314His is P/LP, and p.Pro314Thr is LP in ClinVar

PP3

In silico do not agree on damaging effect. REVEL=0.782

Curation History

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