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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CA16020786

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e545334a-7c8c-4e24-9cb1-c5e150baa8d8

HGVS expressions

NM_001354304.2:c.441+2T>A

NC_000012.12:g.102877460A>T

CM000674.2:g.102877460A>T

NC_000012.11:g.103271238A>T

CM000674.1:g.103271238A>T

NC_000012.10:g.101795368A>T

NG_008690.1:g.45143T>A

NG_008690.2:g.85951T>A

NM_000277.1:c.441+2T>A

NM_000277.2:c.441+2T>A

NM_001354304.1:c.441+2T>A

NM_000277.3:c.441+2T>A

ENST00000307000.7:c.426+2T>A

ENST00000549111.5:n.537+2T>A

ENST00000550978.6:n.427T>A

ENST00000551988.5:n.530+2T>A

ENST00000553106.5:c.441+2T>A

Pathogenic

PM3_Supporting PVS1 PP4_Moderate PM2

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.441+2T>A (aka IVS4+2T>A) variant in PAH has been observed in at least two patients with PAH deficiency (PMID: 26503515, 23932990, and 19915519). The variant was observed with pathogenic variant p.Y356X; phase unknown. This variant is absent from controls in population databases. This variant in the +2 splice donor site of intron 4 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay. This variant breaks the splice site in intron 4 according to computational models. In summary, this variant meets criteria to be classified as pathogenic in PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting and PP4_moderate.

PM3_Supporting

[IVS4+2T>A];p.[Y356X]. Phase unknown. PMID: 23932990

PVS1

This variant in the +2 splice donor site of IVS4 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD), as it is not located in the last exon or the last 50 bp of the preliminary exon. This variant breaks the splice site in IVS4 according to Splice AI (0.91- splice altering) and TraP (0.894, >99%ile, probably damaging).

PP4_Moderate

This variant was observed in at least two patients with Phe >120 µmol/L. Exact diagnoses and Phe levels were not given. BH4 deficiency was excluded through dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and a tetrahydrobiopterin loading test. It is unclear whether these patients overlap with those described in Zhu 2010 and Zhu 2013. PMID: 26503515, 23932990, and 19915519

PubMed:23932990

PubMed:26503515

PubMed:19915519

PM2

This variant is absent from controls in gnomAD, ExAC, and 1000 Genomes population databases.

Approved on: 2020-10-23

Published on: 2020-10-23

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