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.472C>T (p.Arg158Trp)

CA229570

102693 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: faad1844-5076-4b6f-b671-eeb06035449a

HGVS expressions

NM_000277.2:c.472C>T
NM_000277.2(PAH):c.472C>T (p.Arg158Trp)
NC_000012.12:g.102866633G>A
CM000674.2:g.102866633G>A
NC_000012.11:g.103260411G>A
CM000674.1:g.103260411G>A
NC_000012.10:g.101784541G>A
NG_008690.1:g.55970C>T
NG_008690.2:g.96778C>T
NM_000277.1:c.472C>T
NM_001354304.1:c.472C>T
NM_000277.3:c.472C>T
ENST00000307000.7:c.457C>T
ENST00000549111.5:n.568C>T
ENST00000551988.5:n.530+10829C>T
ENST00000553106.5:c.472C>T

Pathogenic

Met criteria codes 5
PM3_Strong PS3 PP4_Moderate PP3 PM2

Expert Panel

Evidence Links 5

Evidence submitted by expert panel
PAH VCEP
PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). 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
PM3_Strong
Detected with 3 pathogenic/likely pathogenic variants

PS3
2% mutant enzyme activity in BioPKU
PP4_Moderate
Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient.

PP3
Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939
PM2
Extremely low frequency. ExAC MAF=0.00019.
Approved on: 2018-08-10
Published on: 2019-04-06
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