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]

Link to SEPIO compliant JSON-LD document

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

CA229402

635 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

Approved on: 2020-08-28

Published on: 2021-02-11

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