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

CA16020836

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0eb5625c-2037-4283-967b-11fb0f54eb44

HGVS expressions

NM_000277.1:c.676C>A

NC_000012.12:g.102855166G>T

CM000674.2:g.102855166G>T

NC_000012.11:g.103248944G>T

CM000674.1:g.103248944G>T

NC_000012.10:g.101773074G>T

NG_008690.1:g.67437C>A

NG_008690.2:g.108245C>A

NM_000277.2:c.676C>A

NM_001354304.1:c.676C>A

NM_000277.3:c.676C>A

NM_001354304.2:c.676C>A

ENST00000307000.7:c.661C>A

ENST00000549111.5:n.772C>A

ENST00000553106.5:c.676C>A

Likely Pathogenic

PM3_Strong PP3 PM2 PP4_Moderate

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.676C>A (p.Gln226Lys) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID 26481238, 29654578). This variant is absent in population databases. This variant was detected in trans with pathogenic variants p.Gln20* and p.Ile306Val. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.

PM3_Strong

PMID 26481238: c.168+5G>C (P 6 submitters) /p.Gln226Lys parental analysis not reported PMID: 29654578: in trans with p.Gln20* (P) and p.Ile306Val (P 4 submitters) segregation analysis performed

PubMed:29654578

PMID 26481238: Table 1 listed c.168+5G>C/p.Gln226Lys in one patient with Phe 1212uM. PubMed:26481238

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster, REVEL=0.868

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PP4_Moderate

PMID 26481238: c.168+5G>C/p.Gln226Lys in one patient with Phe 1212uM. Pterin concentrations were measured from dried blood spots using a HPLC method for pterins. DHPR activity was measured from dried blood spots by enzyme assay.

PMID 26481238: Table 1 listed c.168+5G>C/p.Gln226Lys in one patient with Phe 1212uM. PubMed:26481238

Approved on: 2020-03-14

Published on: 2020-03-15

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