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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CA16020808

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 778c918a-02b3-490f-9fa2-c1612174ff3c

HGVS expressions

NM_001354304.2:c.510-1G>A

NC_000012.12:g.102855333C>T

CM000674.2:g.102855333C>T

NC_000012.11:g.103249111C>T

CM000674.1:g.103249111C>T

NC_000012.10:g.101773241C>T

NG_008690.1:g.67270G>A

NG_008690.2:g.108078G>A

NM_000277.1:c.510-1G>A

NM_000277.2:c.510-1G>A

NM_001354304.1:c.510-1G>A

NM_000277.3:c.510-1G>A

ENST00000307000.7:c.495-1G>A

ENST00000549111.5:n.606-1G>A

ENST00000551988.5:n.531-1G>A

ENST00000553106.5:c.510-1G>A

Pathogenic

PVS1 PP4 PM2 PM3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.510-1G>A variant in PAH is a canonical splice acceptor in which exon skipping disrupts the reading frame and is predicted to undergo nonsense mediated-decay. This variant was detected in a patient with classic PKU in an Australian cohort with the pathogenic variant c.1066-11G>A (PMID 24368688). 2 patients in a Chinese Han PKU cohort were identified with c.510-1G>A in trans with pathogenic variant p.Arg241Cys and VUS p.Ile421Thr. (PMID 28982351). This variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4.

PVS1

This variant is in the -1 acceptor site of IVS5. This results in exon skipping that disrupts reading frame. Predicted to undergo NMD, not located in the last exon or last 50bp of preliminary exon. Altered region is critical to protein function. Number of pathogenic non-nonsense variants in skipped exon: 33. Variant removes more than 10% of transcript (14.5% of transcript.)

PP4

A patient in an Australian cohort with pathogenic variant c.1066-11G>A was documented with classic PKU (>1,200 µmol/L). A BH4 loading test was completed for previous variants in Mitchell et al.,2005, but not for this variant (PMID 24368688). Two patients in a Chinese Han cohort were documented, one heterozygous with p.arg241cys and classic PKU and another patient with mHP (200-600 μmol/L) was heterozygous with the unclassified variant p.Ile421Thr. Patients with BH4 cofactor deficiency were excluded, methodology of BH4 exclusion was not specified (PMID 29316886).

PM2

This variant is absent from databases such as 1000G, ESP, and gnomAD.

PM3

This variant was detected in a patient with classic PKU in an Australian cohort with the pathogenic variant c.1066-11G>A. Control screening was done for this variant. Parental analysis was not reported for the patient confirm compound heterozygosity (PMID 24368688). 2 patients in a Chinese Han cohort were identified with PKU, one with the pathogenic variant p.arg241cys and the second with uncertain significance/not classified variant p.Ile421Thr. Parental analysis was completed confirm compound heterozygosity (PMID 28982351).

Approved on: 2020-07-24

Published on: 2020-07-24

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