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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.581T>C (p.Leu194Pro)

CA229633

102742 (ClinVar)

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

HGVS expressions

NM_000277.2:c.581T>C
NM_000277.1:c.581T>C (p.Leu194Pro)
XM_011538422.1:c.581T>C (p.Leu194Pro)
NM_001354304.1:c.581T>C (p.Leu194Pro)
XM_017019370.2:c.581T>C (p.Leu194Pro)
ENST00000307000.7:c.566T>C (p.Leu189Pro)
ENST00000549111.5:n.677T>C
ENST00000553106.5: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

Likely Pathogenic

Met criteria codes 4
PP3 PM2 PM3_Strong PP4_Moderate

Expert Panel

Evidence Links 4

Evidence submitted by expert panel
PAH EP
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
PP3
Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.899
PM2
Absent from 1000G, ESP. gnomAD MAF:0.00004.
PM3_Strong
Detected in trans with V245A and R261X, both pathogenic

PP4_Moderate
Detected in 3 patients (1 HPA, 1 PKU). BH4 deficiency excluded in 2 patients.

Approved on: 2018-08-13
Published on: 2018-10-02
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