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]

Variant: NM_001354304.2:c.548A>G

CA16020814

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 89040e57-f09d-4602-82a0-0051fcd93944

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_001354304.2:c.548A>G

NC_000012.12:g.102855294T>C

CM000674.2:g.102855294T>C

NC_000012.11:g.103249072T>C

CM000674.1:g.103249072T>C

NC_000012.10:g.101773202T>C

NG_008690.1:g.67309A>G

NG_008690.2:g.108117A>G

ENST00000553106.6:c.548A>G

ENST00000307000.7:c.533A>G

ENST00000549111.5:n.644A>G

ENST00000551988.5:n.569A>G

ENST00000553106.5:c.548A>G

NM_000277.1:c.548A>G

NM_000277.2:c.548A>G

NM_001354304.1:c.548A>G

NM_000277.3:c.548A>G

Pathogenic

PP4_Moderate PS3_Supporting PM3_Strong PP3_Strong PM2_Supporting

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.548A>G (p.Glu183Gly) variant in PAH was reported in trans with pathogenic variants p.Arg111* and c.721C>T in 2 patients with PAH deficiency (>120 μmol/L Phe, BH4 deficiency excluded) (PMID: 28982351, 28754886). Residual enzyme activity was 9.1% for p.Glu183Gly compared to the wild-type PAH (PMID: 24327145). Computational evidence for this missense variant is predicted to be damaging (REVEL=0.977). This variant is absent from population databases gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2_supporting, PP4_moderate, PP3_strong, PS3_supporting.

PP4_Moderate

Detected in 2 patients with PAH deficiency (>120umol/L Phe). BH4 deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay for 1 patient. PMID: 28982351, 28754886

PS3_Supporting

Expression vectors containing PAH cDNA were constructed, residual enzyme activity was measured and found to be 9.1% for p.Glu183Gly compared to the wild-type PAH. Information from the abstract. PMID: 24327145

PM3_Strong

This variant was detected 2 times in trans with pathogenic PAH variants p.Arg111* (1.0pts) and c.721C>T (1.0pts) PMID: 28982351, 28754886

PP3_Strong

Computational evidence for this missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease causing (MutationTaster). REVEL=0.977.

PM2_Supporting

This variant is absent from population databases gnomAD, 1000 Genomes, and ESP

PM5

p.Glu183Leu is classified as likely pathogenic

Curation History

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