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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CA16020995

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6f43b73e-a3ab-4c22-8a41-b6e84e007afd

HGVS expressions

NM_000277.3:c.1315+5G>C

NC_000012.12:g.102840395C>G

CM000674.2:g.102840395C>G

NC_000012.11:g.103234173C>G

CM000674.1:g.103234173C>G

NC_000012.10:g.101758303C>G

NG_008690.1:g.82208G>C

NG_008690.2:g.123016G>C

NM_000277.1:c.1315+5G>C

NM_000277.2:c.1315+5G>C

NM_001354304.1:c.1315+5G>C

ENST00000307000.7:c.1300+5G>C

ENST00000551114.2:n.977+5G>C

ENST00000553106.5:c.1315+5G>C

ENST00000635477.1:n.419+5G>C

ENST00000635528.1:n.830+5G>C

Uncertain Significance

PP4_Moderate PP3 PM2

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.1315+5G>C variant in PAH is absent from population databases (PM2) and human splice finder and MaxEnt Scan predict a deleterious effect on the WT donor splice site (PM3). It has been observed in at least 2 moderate or classic PKU patients with BH4 deficiency excluded (PMID: 30747360; PP4_moderate). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4_moderate.

PP4_Moderate

(PMID: 30747360) Three c.1315+5G>A alleles were identified; 2 in classic PKU case(s) (Phe ≥ 1200 μmol/L) and one in a moderate case (Phe: 360 ~ 1200 μmol/L). For all patients tetrahydrobiopterin deficiency was excluded through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay on DBS samples.

PubMed:30747360

PP3

Multiple lines of computation evidence agree that there is alteration of the WT donor site, most probably affecting splicing. Human splice finder predicts alteration of WT donor site with -14.36% variation, MaxEnt Scan predicts -80.83% variation.

PM2

This variant is absent from all populations in gnomAD ExAC, 1000 Genomes, and ESP.

PM3

At least 3 patients have been identified with this variant on one allele (PMID: 29499199, PMID: 30747360) however the genotypes were not specified for each patient, as such the second allele can not be identified.

PubMed:29499199

Approved on: 2019-12-22

Published on: 2019-12-23

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