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]

Link to SEPIO compliant JSON-LD document

CA16020722

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 92f4145f-90b2-44d1-b957-41f2e3db9d03

HGVS expressions

NM_000277.1:c.60+4A>T

NC_000012.12:g.102917067T>A

CM000674.2:g.102917067T>A

NC_000012.11:g.103310845T>A

CM000674.1:g.103310845T>A

NC_000012.10:g.101834975T>A

NG_008690.1:g.5536A>T

NG_008690.2:g.46344A>T

NM_000277.2:c.60+4A>T

NM_001354304.1:c.60+4A>T

NM_000277.3:c.60+4A>T

ENST00000307000.7:c.-88+4A>T

ENST00000546844.1:c.60+4A>T

ENST00000547319.1:n.371+4A>T

ENST00000549111.5:n.156+4A>T

ENST00000550978.6:n.44+4A>T

ENST00000551337.5:c.60+4A>T

ENST00000551988.5:n.149+4A>T

ENST00000553106.5:c.60+4A>T

ENST00000635500.1:n.29-4169A>T

Likely Pathogenic

PP3 PP4 PM3 PM2

BP7 BP4

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

Likely pathogenic: The c. 60+4A>T was reported in two patients with PKU, who carried a second pathogenic variant (PMID: 17502162, parental studies not reported). Further, computational splice site algorithms predict a reduction at the donor site of intron 1. This variant is absent from population databases, including 1000 Genomes, ESP, and gnomAD. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP3, PP4.

PP3

Alamut software: "Predicted change at donor site 4 bps upstream: -29.0% "

PP4

Detected in 2 PKU patients (PMID: 17502162). BH4 deficiencies not assessed

Twenty original newborn screening DBS specimens were recovered from an archive. c.60+4C>T was identified in 2 patients (Table 5: sample 24 and 63) PubMed:17502162

PM3

Detected with 2 known pathogenic variants (PMID: 17502162). Parental studies not reported.

Table 5: Variant observed in two compound heterozygote PKU patients, both in trans with a ClinVar pathogenic variant (c.1066-11G>A; c.842C>T Var 589). PubMed:17502162

PM2

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

BP7

Dog has a "C" at this position. Otherwise conserved to Cape golden mole (UCSC genome browser).

BP4

Alamut software: "Predicted change at donor site 4 bps upstream: -29.0% "

Approved on: 2019-08-11

Published on: 2019-08-11

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