Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.2(PAH):c.187A>C (p.Thr63Pro)

CA229473

102619 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: cb8e3701-5523-4f65-afc4-045cb61b8851

HGVS expressions

NM_000277.2:c.187A>C

NM_000277.2(PAH):c.187A>C (p.Thr63Pro)

NC_000012.12:g.102894900T>G

CM000674.2:g.102894900T>G

NC_000012.11:g.103288678T>G

CM000674.1:g.103288678T>G

NC_000012.10:g.101812808T>G

NG_008690.1:g.27703A>C

NG_008690.2:g.68511A>C

NM_000277.1:c.187A>C

NM_001354304.1:c.187A>C

NM_000277.3:c.187A>C

ENST00000307000.7:c.172A>C

ENST00000546844.1:c.187A>C

ENST00000548677.2:n.274A>C

ENST00000548928.1:n.109A>C

ENST00000549111.5:n.283A>C

ENST00000550978.6:n.171A>C

ENST00000551337.5:c.187A>C

ENST00000551988.5:n.276A>C

ENST00000553106.5:c.187A>C

ENST00000635500.1:n.155A>C

Uncertain Significance

PM2 PP4_Moderate

PP3 PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.187A>C (p.Thr63Pro) variant in PAH was detected in 1 Danish PKU patient (Phenylalanine > 600 umol/L). Other causes of hyperphenylalaninemia had been ruled out. (PMID: 8406445). It was in cis with a p.H64N variant (No assertion provided, ClinVar). The c.187A>C variant is absent from ExAC, gnomAD, 1000G, and ESP. There are conflicting predictions of pathogenicity: SIFT:T,D; Polyphen2:D,P; MutationTaster:Disease causing; REVEL:0.768. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate.

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

T63P/H64N was detected in 1 Danish PKU patient (Phe > 600 umol/L). Other causes of hyperphenylalaninemia had been ruled out. PMID: 8406445

PKU patients and family members from 135 unrelated Danish familes. Patients were diagnosed when their serum Phe levels exceeded 600 umol/L before treatment and when other causes of hyperphenylalaninemia had been ruled out. T63P was detected on 1 allele. (Fig1, lane 4). PubMed:8406445

PP3

Conflicting predictions of pathogenicity: SIFT:T,D; Polyphen2:D,P; MutationTaster:Disease causing. REVEL:0.768

PM5

only variant found in this codon in ClinVar

Approved on: 2018-12-10

Published on: 2019-04-06

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