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_000277.3(PAH):c.547G>C (p.Glu183Gln)

CA229619

102732 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: c8401640-e3b4-4b3c-a751-b118f875fed1

Approved on: 2025-11-29

Published on: 2025-11-29

HGVS expressions

NM_000277.3(PAH):c.547G>C (p.Glu183Gln)

NM_000277.3:c.547G>C

NC_000012.12:g.102855295C>G

CM000674.2:g.102855295C>G

NC_000012.11:g.103249073C>G

CM000674.1:g.103249073C>G

NC_000012.10:g.101773203C>G

NG_008690.1:g.67308G>C

NG_008690.2:g.108116G>C

ENST00000553106.6:c.547G>C

ENST00000307000.7:c.532G>C

ENST00000549111.5:n.643G>C

ENST00000551988.5:n.568G>C

ENST00000553106.5:c.547G>C

NM_000277.1:c.547G>C

NM_000277.2:c.547G>C

NM_001354304.1:c.547G>C

NM_001354304.2:c.547G>C

Likely Pathogenic

PM3_Supporting PM5_Supporting PP3_Strong PP4 PM2_Supporting

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

The NM_000277.1(PAH):c.547G>C (p.Glu183Gln) variant is a missense variant predicted to cause substitution of glutamate by glutamine at amino acid 183 (p.Glu183Gln). This variant has been detected in one individual with classic phenylketonuria. This patient was compound heterozygous for the variant and a pathogenic variant, R408W. Parental testing not noted to have been performed (PM3_supporting; PMID:24350308). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.939, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong). Another missense variant (c.547_548delinsTT, p.E183L) in the same codon has been classified as likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PM3_supporting, PP4, PP3_strong, PM5_supporting. Version 2.0, 7/16/2024.

PM3_Supporting

This variant has been detected in one individual with Phenylketonuria. This patient was compound heterozygous for the variant and a pathogenic variant, R408W. Parental testing not noted to have been performed (PM3_supporting; PMID:24350308).

PM5_Supporting

Another missense variant (c.547_548delinsTT, p.E183L) in the same codon has been classified as likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5_Supporting).

PP3_Strong

The computational predictor REVEL gives a score of 0.939, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong).

PP4

At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) (PP4).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

Curation History

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