Variant: NM_000277.3(PAH):c.451G>C (p.Asp151His)

CA229553

102682 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: d15d8248-230b-4443-917e-6869c8e4e146

Approved on: 2024-11-17

Published on: 2024-11-17

HGVS expressions

NM_000277.3:c.451G>C
NM_000277.3(PAH):c.451G>C (p.Asp151His)
NC_000012.12:g.102866654C>G
CM000674.2:g.102866654C>G
NC_000012.11:g.103260432C>G
CM000674.1:g.103260432C>G
NC_000012.10:g.101784562C>G
NG_008690.1:g.55949G>C
NG_008690.2:g.96757G>C
ENST00000553106.6:c.451G>C
ENST00000307000.7:c.436G>C
ENST00000549111.5:n.547G>C
ENST00000551988.5:n.530+10808G>C
ENST00000553106.5:c.451G>C
NM_000277.1:c.451G>C
NM_000277.2:c.451G>C
NM_001354304.1:c.451G>C
NM_001354304.2:c.451G>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM5_Supporting PP3_Strong

• Not Met criteria codes: PP4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.451G>C (p.Asp151His) variant in PAH is reported in a phenylketonuria cohort of the British Isles (PMID: 9012412). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect (REVEL=0.977). Another missense variant [c.452A>G (p.Asp151Gly)] in the same codon has been classified as likely pathogenic for phenylketonuria by the ClinGen Phenylketonuria Variant Curation Expert Panel (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3_strong, PM5_supporting.

Met criteria codes

• PM2_Supporting: absent from gnomAD v4.1.0
• PM5_Supporting: D151G in ClinVar is LP by PAH VCEP
• PP3_Strong: Predicted deleterious in REVEL=0.977, SIFT, PP-2, MutationTaster

Not Met criteria codes

• PP4: Reported in a PKU cohort in the British Isles, no serum Phe cutoff given, no BH4 assessment reported PMID: 9012412