The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Criteria Specification: CSpec Registry PDF

Variant: NM_000277.2(PAH):c.533A>G (p.Glu178Gly)

CA273110

92746 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 9cbb36d6-2daf-4507-b947-3a692ec4d9e7

HGVS expressions

NM_000277.2:c.533A>G
NM_000277.2(PAH):c.533A>G (p.Glu178Gly)
NC_000012.12:g.102855309T>C
CM000674.2:g.102855309T>C
NC_000012.11:g.103249087T>C
CM000674.1:g.103249087T>C
NC_000012.10:g.101773217T>C
NG_008690.1:g.67294A>G
NG_008690.2:g.108102A>G
NM_000277.1:c.533A>G
NM_001354304.1:c.533A>G
NM_000277.3:c.533A>G
ENST00000307000.7:c.518A>G
ENST00000549111.5:n.629A>G
ENST00000551988.5:n.554A>G
ENST00000553106.5:c.533A>G

Pathogenic

Met criteria codes 5
PS3 PP3 PP4_Moderate PM2 PM3_Strong

Expert Panel

Evidence Links 3

Evidence submitted by expert panel
PAH VCEP
PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. ExAC MAF=0.00017; PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.841; PS3: 39% residual phenylalanine hydroxylase activity (PMID:17935162); PP4_Moderate: Detected in 6 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen PAHEP. (PMID:18294361; PMID:9634518); PM3_Strong: In trans with 3 pathogenic variants (PMID:18294361). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong).
Met criteria codes
PS3
39% residual phenylalanine hydroxylase activity

PP3
Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.841
PP4_Moderate
Detected in 6 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen PAHEP.

PM2
Absent from 1000G, ESP. ExAC MAF=0.00017
PM3_Strong
In trans with 3 pathogenic variants

Approved on: 2018-08-10
Published on: 2019-04-06
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