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]

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Variant: NM_000277.2(PAH):c.789C>G (p.Phe263Leu)

CA229760

102833 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: aa0c5a96-1385-4b9c-ae8b-d8cb6898d847

HGVS expressions

NM_000277.2:c.789C>G

NM_000277.2(PAH):c.789C>G (p.Phe263Leu)

NC_000012.12:g.102852868G>C

CM000674.2:g.102852868G>C

NC_000012.11:g.103246646G>C

CM000674.1:g.103246646G>C

NC_000012.10:g.101770776G>C

NG_008690.1:g.69735C>G

NG_008690.2:g.110543C>G

NM_000277.1:c.789C>G

NM_001354304.1:c.789C>G

NM_000277.3:c.789C>G

ENST00000307000.7:c.774C>G

ENST00000549247.6:n.548C>G

ENST00000553106.5:c.789C>G

Uncertain Significance

PP3 PM2 PP4_Moderate

PM5 PM3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.789C>G (p.Phe263Leu) variant in PAH is reported in 1 patient with classical PKU, and 1 Chinese PKU patient. (BH4 deficiency excluded. PMID: 8222245, 26600521) This variant is absent from 1000G and ESP with extremely low frequency in ExAC/gnomAD (MAF=0.00003). It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.929. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3.

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.929.

PM2

Absent from 1000G, ESP. Extremely low frequency in ExAC, gnomAD (MAF=0.00003)

PP4_Moderate

F263L seen in 1 patient with classical PKU, and 1 Chinese PKU patient. BH4 deficiency excluded. PMID: 8222245, 26600521

All the probands had abnormal blood Phe concentrations (>120 μM) and had differential diagnosis detected by BH4-loading test, excluding BH4 deficiency. F263L was found on 1 PKU allele. PubMed:26600521

Caucasian patient with classical PKU bearing a novel F263L transversion in exon 7. a heterozygous C-to-G transversion at the third base of codon 263, resulting in a substitution of Phe for Lou in the protein of the patient’s sample (Figure IA). DNA fragments of amplified exon 7 were used for hybridization with allele-specific oligonudeotides. The patient’s sample hybridized with both normal and mutant probes, whereas the control sample reacted only with the normal probe (Figure 1B). PubMed:8222245

PM5

This is the only variant found in this codon in ClinVar.

PM3

Detected in trans with R400T

Family 72: Proband F263L (Paternal) /R400T (Maternal, no assertion provided in ClinVar) PubMed:26600521

Approved on: 2018-12-10

Published on: 2019-04-05

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