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_000277.1:c.686A>G

CA16020839

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 09de0d52-2b52-43a4-b23e-0c282bea2795

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000277.1:c.686A>G

NC_000012.12:g.102855156T>C

CM000674.2:g.102855156T>C

NC_000012.11:g.103248934T>C

CM000674.1:g.103248934T>C

NC_000012.10:g.101773064T>C

NG_008690.1:g.67447A>G

NG_008690.2:g.108255A>G

ENST00000553106.6:c.686A>G

ENST00000307000.7:c.671A>G

ENST00000549111.5:n.782A>G

ENST00000553106.5:c.686A>G

NM_000277.2:c.686A>G

NM_001354304.1:c.686A>G

NM_000277.3:c.686A>G

NM_001354304.2:c.686A>G

Likely Pathogenic

PM2_Supporting PS3_Supporting PP3_Moderate PP4 PM3_Supporting

Evidence Links 2

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

The c.686A>G (p.Asp229Gly) variant in PAH has been reported in 1 individual with PAH deficiency, detected with pathogenic variant p.R408W (PMID: 23357515). This variant is absent in population databases. Computational evidence supports a deleterious effect (REVEL=0.922). Functional studies show the p.Asp229Gly mutant had 0% residual activity as compared to WT PAH activity and decreased protein levels (PMID: 31208052). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PP4, PM2_supporting, PM3_supporting, PP3_moderate.

PM2_Supporting

Absent from ExAC, gnomAD, 1000G, ESP

PS3_Supporting

p.Asp229Gly had 0% residual activity as compared to WT PAH activity and was calculated as a mean of nine independent functional assays. Western blot analysis revealed decreased protein levels of each tested PAH mutant cultivated under both conditions compared to WT PAH. The overall results were calculated from three independent Western blot analyses performed from three independent PAH expressions in HepG2 cells. PMID: 31208052

The p.Asn167Tyr, p.Thr200Asn, p.Asp229Gly, p.Gly239Ala, p.Phe263Ser, p.Ala342Pro, and p.Ile406Met PAH variants were expressed in prokaryotic and eukaryotic expression systems and assayed in vitro to investigate their specific activity, oligomeric pattern, and the mutant PAH protein stability in the presence of sepiapterin, which is the BH4 precursor, as well as GroEL/ES bacterial chaperones. p.Asp229Gly had 0% residual activity as compared to WT PAH activity and was calculated as a mean of nine independent functional assays. Western blot analysis revealed decreased protein levels of each tested PAH mutant cultivated under both conditions compared to WT PAH. The overall results were calculated from three independent Western blot analyses performed from three independent PAH expressions in HepG2 cells. PubMed:31208052

PP3_Moderate

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.922

PP4

Seen in 1 patient with Non-PKU HPA (Phe between 120 and 600 μmol/L). BH4 deficiency not excluded. PMID: 23357515

665 unrelated Czech HPA patients. c.686A>G, p.(Asp229Gly) seen on 1 allele of a Non-PKU HPA patient ((Phe between 120 and 600 μmol/L). PubMed:23357515

PM3_Supporting

Detected with R408W, Pathogenic in ClinVar, parental analysis not reported PMID: 23357515

Seen in 1 Non-PKU HPA patient with the genotype p.[Asp229Gly];[Arg408Trp]. PubMed:23357515

Curation History

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