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_000277.3(PAH):c.1204T>C (p.Phe402Leu)

CA229396

102566 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0979bb04-570d-4e72-8888-0071c2bc5bd4

HGVS expressions

NM_000277.3:c.1204T>C

NM_000277.3(PAH):c.1204T>C (p.Phe402Leu)

NM_000277.1:c.1204T>C

NM_000277.2:c.1204T>C

NM_001354304.1:c.1204T>C

NM_001354304.2:c.1204T>C

ENST00000307000.7:c.1189T>C

ENST00000551114.2:n.866T>C

ENST00000553106.5:c.1204T>C

ENST00000635477.1:n.308T>C

ENST00000635528.1:n.719T>C

NC_000012.12:g.102840511A>G

CM000674.2:g.102840511A>G

NC_000012.11:g.103234289A>G

CM000674.1:g.103234289A>G

NC_000012.10:g.101758419A>G

NG_008690.1:g.82092T>C

NG_008690.2:g.122900T>C

Uncertain Significance

PM2 PM3_Supporting PP4

PM5 PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1204T>C (p.Phe402Leu) variant in PAH has been F402L detected in 1 Croatian patient with mild PKU, serum Phe = 600-1200 umol/L, BH4 deficiency not excluded (PMID: 12655552;PP4). This variant was detected with c.1169A>G (p.Glu390Gly) in this patient, reported as Pathogenic in ClinVar, VarID: 625, phase unknown (PMID: 12655552; PM3_Supporting). This variant is absent from population databases (PM2), and computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4, PM3.

PM2

Variant absent from population databases.

PM3_Supporting

PMID: 12655552 - F402L detected with c.1169A>G (p.Glu390Gly) in 1 Croatian patient, reported as Pathogenic in ClinVar, VarID: 625, phase unknown - 0.5 points

PubMed:12655552

PP4

PMID: 12655552 - F402L detected in 1 Croatian patient with mild PKU, serum Phe = 600-1200 umol/L, BH4 deficiency not excluded

PM5

At same codon as c.1204T>A (p.F402I), c.1204T>G (p.F402V), and c.1205T>G (p.F402V) - all curated as VUS by ClinGen PAH VCEP.

PP3

Computational evidence is conflicting. Predicted deleterious by SIFT, MutationTaster and REVEL = 0.918, but is predicted benign by PholyPhen2.

Approved on: 2020-08-27

Published on: 2020-08-27

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