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

CA229396

102566 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

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

Approved on: 2024-11-17

Published on: 2024-11-18

HGVS expressions

NM_000277.3:c.1204T>C
NM_000277.3(PAH):c.1204T>C (p.Phe402Leu)
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
ENST00000553106.6:c.1204T>C
ENST00000307000.7:c.1189T>C
ENST00000551114.2:n.866T>C
ENST00000553106.5:c.1204T>C
ENST00000635477.1:c.308T>C
ENST00000635528.1:n.719T>C
NM_000277.1:c.1204T>C
NM_000277.2:c.1204T>C
NM_001354304.1:c.1204T>C
NM_001354304.2:c.1204T>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP3_Moderate PP4 PM3

• Not Met criteria codes: PM5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1204T>C (p.Phe402Leu) variant in PAH has been 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), and has also been reported in unknown phase with the pathogenic p.Arg408Gln variant (ClinVar ID: 577) in another individual with PAH deficiency (PMID: 32668217) (1pt total, PM3). This variant is absent from population databases (PM2_Supporting), and is predicted damaging by REVEL (REVEL score 0.918, PP3_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM3, PP3_Moderate, PP4.

Met criteria codes

• PM2_Supporting: Variant absent from gnomAD v4.1.0
• PP3_Moderate: Computational evidence is conflicting. Predicted deleterious by SIFT, MutationTaster and REVEL = 0.918, but is predicted benign by PholyPhen2.
• PP4: PMID: 12655552 - F402L detected in 1 Croatian patient with mild PKU, serum Phe = 600-1200 umol/L, BH4 deficiency not excluded
• PM3: 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. PMID: 32668217: 1 pku case, genotype p.F402/R408Q, phase not confirmed. R408Q is path in ClinVar (ID: 577). Total 1pt, PM3_Moderate

Not Met criteria codes

• 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.