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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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Criteria Specification: CSpec Registry PDF

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

CA220584

92743 (ClinVar)

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

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 3
PP4_Moderate PM2 PM3_Strong
Unmet criteria codes 1
PP3

Expert Panel

Evidence Links 4

Evidence submitted by expert panel
PAH 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
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
PM3_Strong
Patient 664 with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants.

Unmet 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
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