Variant: NM_000277.2(PAH):c.500A>T (p.Asn167Ile)

CA220584

92743 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: a49cb655-9cb0-4fac-959d-26d4290227d6

HGVS expressions

NM_000277.2:c.500A>T
NM_000277.2(PAH):c.500A>T (p.Asn167Ile)
NC_000012.12:g.102866605T>A
CM000674.2:g.102866605T>A
NC_000012.11:g.103260383T>A
CM000674.1:g.103260383T>A
NC_000012.10:g.101784513T>A
NG_008690.1:g.55998A>T
NG_008690.2:g.96806A>T
NM_000277.1:c.500A>T
NM_001354304.1:c.500A>T
NM_000277.3:c.500A>T
ENST00000307000.7:c.485A>T
ENST00000549111.5:n.596A>T
ENST00000551988.5:n.530+10857A>T
ENST00000553106.5:c.500A>T

Likely Pathogenic

• Met criteria codes: PM3_Strong PP4_Moderate PM2

• Not Met criteria codes: PP3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (MAF=0.00003). Absent from gnomAD, 1000G, ESP; PP4_Moderate: Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. (PMID:26666653; PMID:9012412; PMID:10679941); PM3_Strong: Patient 664 with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants. (PMID:24368688; PMID:26666653). 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, PP4_Moderate, PM3_Strong).

Met criteria codes

• PM3_Strong: Patient 664 with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants.
• PP4_Moderate: Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity.
• PM2: Extremely low frequency in ExAC (MAF=0.00003). Absent from gnomAD, 1000G, ESP

Not Met criteria codes

• PP3: Conflicting predictions of pathogenicity: Damaging in SIFT, MutationTaster, Benign in Polyphen, REVEL=0.645.

Approved on: 2018-08-28

Published on: 2019-04-06