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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CA16020872

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 19aa2f2d-1c0d-4009-8057-c7dadf83c426

Approved on: 2019-04-03

Published on: 2019-08-16

HGVS expressions

NM_000277.3:c.842+6T>A

NC_000012.12:g.102852809A>T

CM000674.2:g.102852809A>T

NC_000012.11:g.103246587A>T

CM000674.1:g.103246587A>T

NC_000012.10:g.101770717A>T

NG_008690.1:g.69794T>A

NG_008690.2:g.110602T>A

NM_000277.1:c.842+6T>A

NM_000277.2:c.842+6T>A

NM_001354304.1:c.842+6T>A

ENST00000307000.7:c.827+6T>A

ENST00000549247.6:n.601+6T>A

ENST00000553106.5:c.842+6T>A

ENST00000635477.1:n.3+6T>A

Uncertain Significance

PP3 PP4 PM2

PM3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.842+6T>A PAH variant has been identified in at least one patient with hyperphenylalaninemia (PMID: 10429004). Serum phenylalanine was considered severe in this patient (>28mg/dl), however without indication of a second PAH variant. This variant is absent from 1000G, ESP, and gnomAD databases. It is intronic in a highly conserved nucleotide, and computation analysis predict a reduction in splicing at the donor site of intron 7. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4, PM2.

PP3

Reduction of 45% in splicing at the donor site of intron 7.

PP4

Placed in severe PKU group with phenylalanine level ~28mg/dl. BH4 deficiency was not ruled out. PMID: 10429004

Placed in sever PKU group with phenylalanine level ~28mg/dl. BH4 deficiency was not ruled out. PubMed:10429004

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3

The genotype is not reported rather consider patients " functionally hemizygous", if they have one mutation that abolish enzyme activity. It is not clear if PM3 could be applied here.

Authors sequence the DNA of females with elevated serum phenylalanine. The genotype is not reported rather consider patients " functionally hemizygous", if they have one mutation that abolish enzyme activity. It is not clear if PM3 could be applied here. PubMed:10429004

Curation History

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