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_000277.3(PAH):c.442-2A>C

CA267655

120276 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7320c311-f198-4823-b4ee-0eb3d2585cec

Approved on: 2020-07-24

Published on: 2020-07-24

HGVS expressions

NM_000277.3:c.442-2A>C

NM_000277.3(PAH):c.442-2A>C

NM_000277.1:c.442-2A>C

NM_000277.2:c.442-2A>C

NM_001354304.1:c.442-2A>C

NM_001354304.2:c.442-2A>C

ENST00000307000.7:c.427-2A>C

ENST00000549111.5:n.538-2A>C

ENST00000551988.5:n.530+10797A>C

ENST00000553106.5:c.442-2A>C

NC_000012.12:g.102866665T>G

CM000674.2:g.102866665T>G

NC_000012.11:g.103260443T>G

CM000674.1:g.103260443T>G

NC_000012.10:g.101784573T>G

NG_008690.1:g.55938A>C

NG_008690.2:g.96746A>C

Pathogenic

PM2 PM3 PVS1 PP4

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.442-2A>C 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 documented in 3 patients with classic PKU (PMID 26666653, 18937047, 9048935). It was detected with pathogenic variants c.1042C>G and p.Tyr204Cys (PMID 18937047, 9048935). This variant is absent in 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.

PM2

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

PM3

This variant was documented in 2 compound heterozygous patients with pathogenic variants c.1042C>G (p.Leu348Val) and p.Tyr204Cys with classic PKU (PMID 18937047, 9048935). This variant was detected homozygous in a patient with classic PKU in a French cohort and parental analysis was not specified (PMID 26666653). Segregation analysis was done (PMID 9048935).

PVS1

This variant is in the -2 acceptor site. This results in exon skipping disrupts reading frame. Predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 5 out of 13 coding exons (5 out of total exons). Altered region is critical to protein function. Number of pathogenic non-nonsense variants in skipped exon: 22. Variant removes more than 10% of transcript (5.0% of transcript.)

PP4

Detected in 3 patients diagnosed with classic PKU, 2 heterozygous and 1 homozygous patient.(PMID: 26666653, 18937047, 9048935) BH4 loading test was completed in the French cohort. (PMID 26666653).

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