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_000277.2(PAH):c.512G>C (p.Gly171Ala)

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CA229599

102717 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fa47c3ea-0e75-4e80-a83e-19d3fb7b4e99

Approved on: 2023-10-13

Published on: 2023-10-13

HGVS expressions

NM_000277.2:c.512G>C

NM_000277.2(PAH):c.512G>C (p.Gly171Ala)

NC_000012.12:g.102855330C>G

CM000674.2:g.102855330C>G

NC_000012.11:g.103249108C>G

CM000674.1:g.103249108C>G

NC_000012.10:g.101773238C>G

NG_008690.1:g.67273G>C

NG_008690.2:g.108081G>C

ENST00000553106.6:c.512G>C

ENST00000307000.7:c.497G>C

ENST00000549111.5:n.608G>C

ENST00000551988.5:n.533G>C

ENST00000553106.5:c.512G>C

NM_000277.1:c.512G>C

NM_001354304.1:c.512G>C

NM_000277.3:c.512G>C

NM_001354304.2:c.512G>C

NM_000277.3(PAH):c.512G>C (p.Gly171Ala)

Likely Pathogenic

PS3_Supporting PM2_Supporting PP3_Moderate PP4_Moderate PM3_Supporting

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.512G>C (p.Gly171Ala) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 7833954, 9634518); detected with IVSl0nt546 (aka c.1066-11G>A PMID: 7833954). This variant is absent in population databases (PM2_supporting). This variant produces 27% enzyme activity as compared to wild type PAH (PMID: 10479481) Computational evidence supports a damaging effect (REVEL=0.947). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PP4_Moderate, PM2_supporting, PP3_moderatePM3_supporting.

PS3_Supporting

27% enzyme activity (PMID: 29653233, PMID: 10479481)

analyzed three novel naturally occurring PAH gene variants: p.Glu178Lys (c.532G>A), p.Val245Met (c.733G>A) and p.Ser250Phe (c.749C>T). Vectors expressing the corresponding PAH variants were generated for expression in E. coli and in HEK293T cells. The RNA expression of the three PAH variants was measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The mutant PAH protein levels were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), western blot and enzyme-linked immunosorbent assay (ELISA). The transcription of the three PAH variants was similar to the wild type PAH gene in HEK293T cells. In contrast, the levels of mutant PAH proteins decreased significantly compared to the wild type control, in both E. coli and HEK293T cells. PubMed:29653233

20-40% enzyme activity, 12 variants tested, none benign PubMed:10479481

PM2_Supporting

Absent from ExAC, gnomAD, 1000G, ESP

PP3_Moderate

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster, REVEL=0.947.

PP4_Moderate

G171A detected in a patient with MHP, defect in tetrahydrobiopterin metabolism was excluded. 2 reports may be of the same patient (PMID: 7833954, 9634518).

G171A was detected in a French patient with mild variant PKU. BH4 deficiency not reported to be ruled out. PubMed:7833954

G171A detected in a patient with MHP. In all patients, hyperphenylalaninemia had been detected by national mass screening programs, and PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism. PubMed:9634518

PM3_Supporting

Detected with IVSl0nt546 (PMID: 7833954). this is c.1066-11G>A (P) per Ref https://pubmed.ncbi.nlm.nih.gov/1301187/ 0.5 points

Patient genotype: G171A / IVSl0nt546. parental DNA not available. PubMed:7833954

Curation History

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