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.1220C>T (p.Pro407Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229402

635 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0b5b1397-d24f-4369-b608-dd9d8cdb4d08

Approved on: 2020-08-28

Published on: 2021-02-11

HGVS expressions

NM_000277.2:c.1220C>T

NM_000277.2(PAH):c.1220C>T (p.Pro407Leu)

NC_000012.12:g.102840495G>A

CM000674.2:g.102840495G>A

NC_000012.11:g.103234273G>A

CM000674.1:g.103234273G>A

NC_000012.10:g.101758403G>A

NG_008690.1:g.82108C>T

NG_008690.2:g.122916C>T

NM_000277.1:c.1220C>T

NM_001354304.1:c.1220C>T

NM_000277.3:c.1220C>T

NM_001354304.2:c.1220C>T

ENST00000307000.7:c.1205C>T

ENST00000551114.2:n.882C>T

ENST00000553106.5:c.1220C>T

ENST00000635477.1:n.324C>T

ENST00000635528.1:n.735C>T

Likely Pathogenic

PP4 PM2 PM3_Strong

PP3 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.1220C>T (p.Pro407Leu) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 9950317, 23357515, 23792259). This variant is absent in population databases. This variant was detected with pathogenic variants: p.F55fs (PMID: 9950317); p.Tyr414Cys (PMID: 23357515); p.Ala403Val (PMID: 23792259); and p.R408W (PMID: 24350308). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_strong.

PP4

Found in one patient with Classic PKU, Phe levels >1,200 umol/L PMID: 9950317, 1 patient with Mild PKU PMID: 23357515, 1 patient with mild HPA PMID: 23792259

PM2

Absent from controls in ExAC,gnomAD, 1000G, ESP.

PM3_Strong

Found in trans with F55fs (pathogenic 6 submitters) maternal segregation confirmed PMID: 9950317 p.Tyr414Cys (P 13 submitters) parental analysis not reported PMID: 23357515; in trans with p.Ala403Val (P 15 submitters) PMID: 23792259; p.R408W(c.1222C>T)/p.P407L(c.1220C>T) parental testing not reported PMID: 24350308 2.5-3.0 pts

PP3

Tolerated in SIFT. predicted deleterious in Polyphen and Automatic disease causing in MutationTaster.

PM5

P407S (Var ID=102568), LP

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.