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.743T>C (p.Leu248Pro)

CA229737

102819 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: cb595139-389e-4fd2-b2b2-cff5bb5547dc

HGVS expressions

NM_000277.2:c.743T>C

NM_000277.2(PAH):c.743T>C (p.Leu248Pro)

NC_000012.12:g.102852914A>G

CM000674.2:g.102852914A>G

NC_000012.11:g.103246692A>G

CM000674.1:g.103246692A>G

NC_000012.10:g.101770822A>G

NG_008690.1:g.69689T>C

NG_008690.2:g.110497T>C

ENST00000553106.6:c.743T>C

ENST00000307000.7:c.728T>C

ENST00000549247.6:n.502T>C

ENST00000553106.5:c.743T>C

NM_000277.1:c.743T>C

NM_001354304.1:c.743T>C

NM_000277.3:c.743T>C

NM_001354304.2:c.743T>C

NM_000277.3(PAH):c.743T>C (p.Leu248Pro)

Uncertain Significance

PP4 PP3 PM2

PM3 PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.743T>C (p.Leu248Pro) variant in PAH was reported in 1 patient with PAH deficiency (>600 μmol/L Phe, PMID: 8807319). Computational evidence for this missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease-causing (MutationTaster). This variant is absent from population databases ExAC, gnomAD, 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4.

PP4

Seen in 1 PKU patient (Phe > 600 umol/l and other causes of HPA had been ruled out) PMID: 8807319

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.966.

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3

Seen with S349sf (c.1047iGTCA) variant not found in ClinVar

PM5

L248R, no clinical significance provided in ClinVar, curated as US by PAH VCEP

Approved on: 2021-01-25

Published on: 2022-06-05

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