NM_000277.1:c.676C>A

CA16020836

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 0eb5625c-2037-4283-967b-11fb0f54eb44

Approved on: 2020-03-14

Published on: 2020-03-15

HGVS expressions

NM_000277.1:c.676C>A
NC_000012.12:g.102855166G>T
CM000674.2:g.102855166G>T
NC_000012.11:g.103248944G>T
CM000674.1:g.103248944G>T
NC_000012.10:g.101773074G>T
NG_008690.1:g.67437C>A
NG_008690.2:g.108245C>A
NM_000277.2:c.676C>A
NM_001354304.1:c.676C>A
NM_000277.3:c.676C>A
NM_001354304.2:c.676C>A
ENST00000307000.7:c.661C>A
ENST00000549111.5:n.772C>A
ENST00000553106.5:c.676C>A

Likely Pathogenic

• Met criteria codes: PP3 PP4_Moderate PM2 PM3_Strong

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.676C>A (p.Gln226Lys) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID 26481238, 29654578). This variant is absent in population databases. This variant was detected in trans with pathogenic variants p.Gln20* and p.Ile306Val. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.

Met criteria codes

• PP3: Predicted deleterious in SIFT, PolyPhen2, MutationTaster, REVEL=0.868
• PP4_Moderate: PMID 26481238: c.168+5G>C/p.Gln226Lys in one patient with Phe 1212uM. Pterin concentrations were measured from dried blood spots using a HPLC method for pterins. DHPR activity was measured from dried blood spots by enzyme assay.
• PM2: Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP
• PM3_Strong: PMID 26481238: c.168+5G>C (P 6 submitters) /p.Gln226Lys parental analysis not reported PMID: 29654578: in trans with p.Gln20* (P) and p.Ile306Val (P 4 submitters) segregation analysis performed