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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

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

CA273110

92746 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance

HGVS expressions

NM_000277.2:c.533A>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
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_000277.2(PAH):c.533A>G (p.Glu178Gly)

Pathogenic

Met criteria codes 5
PP4_Moderate PM3_Strong PS3 PP3 PM2

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
PP4_Moderate
Detected in 6 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen PAHEP.

PM3_Strong
In trans with 3 pathogenic variants

PS3
39% residual phenylalanine hydroxylase activity

PP3
Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.841
PM2
Absent from 1000G, ESP. ExAC MAF=0.00017
Approved on: 2018-08-10
Published on: 2019-04-06
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