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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Variant: NM_001354304.2:c.599C>A

CA16020825

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 840d4e9c-f699-4de3-8eee-68e68770e52f

Approved on: 2020-12-07

Published on: 2022-03-11

HGVS expressions

NM_001354304.2:c.599C>A

NC_000012.12:g.102855243G>T

CM000674.2:g.102855243G>T

NC_000012.11:g.103249021G>T

CM000674.1:g.103249021G>T

NC_000012.10:g.101773151G>T

NG_008690.1:g.67360C>A

NG_008690.2:g.108168C>A

ENST00000553106.6:c.599C>A

ENST00000307000.7:c.584C>A

ENST00000549111.5:n.695C>A

ENST00000553106.5:c.599C>A

NM_000277.1:c.599C>A

NM_000277.2:c.599C>A

NM_001354304.1:c.599C>A

NM_000277.3:c.599C>A

Uncertain Significance

PP4 PM2 PM3_Supporting

PS3 PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.599C>A (p.Thr200Asn) variant in PAH was reported in 1 patient with PAH deficiency referred to as non-PKU HPA (120 - 600uMol/L Phe), detected with pathogenic variant p.Arg243* (PMID: 23357515). Computational evidence for this variant is conflicting; predicted to be damaging (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant is absent from population databases gnomAD, 1000 Genomes, and ESP. Functional studies have been reported with no major impact on enzyme activity as compared to wild type (PMID: 31208052). In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3 supporting, PP4.

PP4

Detected in a patient with PAH deficiency referred to as non-PKU HPA (120 - 600uMol/L Phe). PMID: 23357515

PM2

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

PM3_Supporting

This variant was detected with the pathogenic PAH variant p.Arg243*. It was not specified whether the parental analysis was performed. PMID: 23357515

PS3

Co-expression with GroEL/ES bacterial chaperones in E.coli was measured and resulted in residual enzymatic activity of 92.4% ± 25.9% which is similar to WT PAH and not significant. Oligomerization, tetramerization and dimerization was measured and resulted in enzymatic activity of 49.0% ± 3.5%, 40.5% ± 6.1% and 10.5% ± 6.3% respectively. These results are consistent with the patient's PAH deficiency phenotype referred to as non-PKU HPA (120-600uMol/L). PMID: 31208052

PP3

Conflicting predictions: Damaging in SIFT and MutationTaster, benign in PolyPhen2

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