Variant: NM_000277.3:c.442G>C

CA16020789

872834 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: ce9b4a37-5fbe-44e5-8560-937945fbfbf1

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000277.3:c.442G>C
NC_000012.12:g.102866663C>G
CM000674.2:g.102866663C>G
NC_000012.11:g.103260441C>G
CM000674.1:g.103260441C>G
NC_000012.10:g.101784571C>G
NG_008690.1:g.55940G>C
NG_008690.2:g.96748G>C
ENST00000553106.6:c.442G>C
ENST00000307000.7:c.427G>C
ENST00000549111.5:n.538G>C
ENST00000551988.5:n.530+10799G>C
ENST00000553106.5:c.442G>C
NM_000277.1:c.442G>C
NM_000277.2:c.442G>C
NM_001354304.1:c.442G>C
NM_001354304.2:c.442G>C

Likely Pathogenic

• Met criteria codes: PM3_Supporting PM2_Supporting PP3_Strong PP4_Moderate PM5_Supporting

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.442G>C (p.Gly148Arg) variant in PAH is a missense variant that is predicted damaging by REVEL (REVEL score 0.947) (PP3_Strong). It is absent from gnomAD v2.1.1 (PM2_Supporting). It has been reported in at least 1 Chinese patient with PAH deficiency with BH4 deficiency excluded (PMID: 26503515, 30050108) (PP4_Moderate), and has been reported in unknown phase with the pathogenic variant p.Arg243Gln (ClinVar ID: 591) (PM3_Supporting). Multiple different missense variants at the same site have been reported likely pathogenic in ClinVar, including c.443G>A (p.Gly148Asp) (ClinVar ID: 872837), c.443G>T (p.Gly148Val) (ClinVar ID: 552657), c.442G>A (p.Gly148Ser) (ClinVar ID: 102680) (PM5_Supporting). 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, PM5_Supporting, PP4_Moderate, PP3_Strong.

Met criteria codes

• PM3_Supporting: 1 patient with mild PKU (plasma Phe 600–1200 μmol/L) and genotype p.R243Q/p.G148R, likely same patient as reported in PMID: 26503515 given author overlap. The p.R243Q variant is path in ClinVar by multiple submitters (ID 591). Parental testing done per PMID: 26503515, but parental genotypes not specified here, and given lack of certainty re case overlap, will count as "presumed trans but phase not confirmed" (0.5pts, PM3_Supporting).
• PM2_Supporting: Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP
• PP3_Strong: REVEL=0.947.
• PP4_Moderate: Detected on 1 allele. Diagnosed through neonatal screening program or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay. PMID: 26503515
• PM5_Supporting: Multiple different missense variants at the same site have been reported likely pathogenic in ClinVar, including c.443G>A (p.Gly148Asp) (ClinVar ID: 872837), c.443G>T (p.Gly148Val) (ClinVar ID: 552657), c.442G>A (p.Gly148Ser) (ClinVar ID: 102680)