Variant: NM_000277.3(PAH):c.1022A>C (p.Lys341Thr)

CA229274

102471 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 00dd024a-b222-4113-9e07-5c75e4156154

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000277.3:c.1022A>C
NM_000277.3(PAH):c.1022A>C (p.Lys341Thr)
NC_000012.12:g.102844379T>G
CM000674.2:g.102844379T>G
NC_000012.11:g.103238157T>G
CM000674.1:g.103238157T>G
NC_000012.10:g.101762287T>G
NG_008690.1:g.78224A>C
NG_008690.2:g.119032A>C
ENST00000553106.6:c.1022A>C
ENST00000307000.7:c.1007A>C
ENST00000549247.6:n.781A>C
ENST00000551114.2:n.684A>C
ENST00000553106.5:c.1022A>C
ENST00000635477.1:c.126A>C
ENST00000635528.1:n.537A>C
NM_000277.1:c.1022A>C
NM_000277.2:c.1022A>C
NM_001354304.1:c.1022A>C
NM_001354304.2:c.1022A>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM5_Supporting PP4 PP3_Strong

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.1022A>C (p.Lys341Thr) variant in PAH has been reported in a patient with PKU (BH4 deficiency not assessed, PMID: 9012412). This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.945. A different likely pathogenic missense change at the same amino acid (p.Lys341Arg) has been seen before. 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, PP4.

Met criteria codes

• PM2_Supporting: Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP
• PM5_Supporting: K341R is LP by PAH VCEP
• PP4: Reported in a patient with PKU. PMID: 9012412
• PP3_Strong: Deleterious effect predicted in SIFT, PolyPhen2, MutationTaster. REVEL=0.945.