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.581T>C (p.Leu194Pro)

CA229633

102742 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 434f1539-4967-4ff7-abc2-e2ff3ca9ecbe

HGVS expressions

NM_000277.2:c.581T>C
NM_000277.2(PAH):c.581T>C (p.Leu194Pro)
NC_000012.12:g.102855261A>G
CM000674.2:g.102855261A>G
NC_000012.11:g.103249039A>G
CM000674.1:g.103249039A>G
NC_000012.10:g.101773169A>G
NG_008690.1:g.67342T>C
NG_008690.2:g.108150T>C
NM_000277.1:c.581T>C
NM_001354304.1:c.581T>C
NM_000277.3:c.581T>C
ENST00000307000.7:c.566T>C
ENST00000549111.5:n.677T>C
ENST00000553106.5:c.581T>C

Likely Pathogenic

Met criteria codes 4
PP4_Moderate PP3 PM3_Strong PM2

Evidence Links 4

Evidence submitted by expert panel
Phenylketonuria VCEP
PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. gnomAD MAF:0.00004.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.899; PM3_Strong: Detected in trans with V245A and R261X, both pathogenic (PMID:7981714; PMID:16601866); PP4_Moderate: Detected in 3 patients (1 HPA, 1 PKU). BH4 deficiency excluded in 2 patients. (PMID:8533759; PMID:7981714; PMID:9012412; PMID:16601866). 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, PP3, PM3_Strong, PP4_Moderate).
Met criteria codes
PP4_Moderate
Detected in 3 patients (1 HPA, 1 PKU). BH4 deficiency excluded in 2 patients.

PP3
Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.899
PM3_Strong
Detected in trans with V245A and R261X, both pathogenic

PM2
Absent from 1000G, ESP. gnomAD MAF:0.00004.
Approved on: 2018-08-13
Published on: 2019-04-06
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