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]

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Variant: NM_000277.3(PAH):c.1150C>T (p.Pro384Ser)

CA16020950

551270 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 21e9cfe6-8ef8-4eff-a4de-f844833071a0

HGVS expressions

NM_000277.3:c.1150C>T

NM_000277.3(PAH):c.1150C>T (p.Pro384Ser)

NC_000012.12:g.102843695G>A

CM000674.2:g.102843695G>A

NC_000012.11:g.103237473G>A

CM000674.1:g.103237473G>A

NC_000012.10:g.101761603G>A

NG_008690.1:g.78908C>T

NG_008690.2:g.119716C>T

ENST00000553106.6:c.1150C>T

ENST00000307000.7:c.1135C>T

ENST00000549247.6:n.909C>T

ENST00000551114.2:n.812C>T

ENST00000553106.5:c.1150C>T

ENST00000635477.1:n.254C>T

ENST00000635528.1:n.665C>T

NM_000277.1:c.1150C>T

NM_000277.2:c.1150C>T

NM_001354304.1:c.1150C>T

NM_001354304.2:c.1150C>T

Uncertain Significance

PP3 PM2

PS3 PP4

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1150C>T (p.Pro384Ser) PAH variant has been reported in at least one “phenylketonuria” or “hyperphenylalaninemia” proband (PMID: 31332730). This variant is absent from 1000G, ESP, and gnomAD databases. It is a missense variant predicted deleterious by Polyphen (probably damaging), MutationTaster (disease causing), and has a REVEL score of 0.902. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3.

PP3

This variant is predicted deleterious by Polyphen (probably damaging), MutationTaster (disease causing), and has a REVEL score of 0.902.

PM2

This variant is absent in population databases including gnomAD, ExAC, 1000 Genomes, or ESP.

PS3

From PMID: 26803807: Expression of a PAH plasmid with the Pro384Ser variant in COS-7 cells resulted in only modestly reduced activity (76%) which does not meet the threshold of <50% activity. Additional in vitro expression studies (PMID: 27620137 and PMID: 31102715) found similar results of 66% activity.

Expression of a PAH plasmid with the Pro384Ser variant in COS-7 cells resulted in only modestly reduced activity (76%) which does not meet the threshold of <50% activity. PubMed:26803807

PP4

PMID: 31332730 describes a proband harboring this Pro384Ser variant with “phenylketonuria” or “hyperphenylalaninemia” with no additional information.

Approved on: 2021-04-23

Published on: 2021-09-06

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