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.749C>T

CA386295701

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 918f78dd-ba44-4fd9-9dd6-6417e8d6b430

Approved on: 2026-04-15

Published on: 2026-04-15

HGVS expressions

NM_001354304.2:c.749C>T

NC_000012.12:g.102852908G>A

CM000674.2:g.102852908G>A

NC_000012.11:g.103246686G>A

CM000674.1:g.103246686G>A

NC_000012.10:g.101770816G>A

NG_008690.1:g.69695C>T

NG_008690.2:g.110503C>T

ENST00000553106.6:c.749C>T

ENST00000307000.7:c.734C>T

ENST00000549247.6:n.508C>T

ENST00000553106.5:c.749C>T

NM_000277.1:c.749C>T

NM_000277.2:c.749C>T

NM_001354304.1:c.749C>T

NM_000277.3:c.749C>T

Likely Pathogenic

PP3_Moderate PP4 PM1 PM2_Supporting

PM3 PS3

Evidence Links 1

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.749C>T variant in PAH is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 250 (p.Ser250Phe). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL), which is highly specific for PAH deficiency (PMID: 28982351). This individual was compound heterozygous for the variant and a variant of uncertain significance confirmed in trans by parental testing (0.25 PM3 points, PM3 does not apply). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant resides within a region, amino acids 246-266, of PAH that is defined as a critical functional domain by the ClinGen PAH Variant Curation Expert Panel (PM1). The computational predictor REVEL gives a score of 0.938, which is above the threshold of 0.644, evidence that correlates with deleterious impact to PAH function; as PM1 is applied PP3 will be applied at the moderate level as not to exceed strong (PP3_moderate). In summary, this variant meets the criteria to be classified as Likely pathogenic for autosomal recessive PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel: PM1, PP3_moderate, PP4, PM2_supporting (PAH VCEP specifications version 2.0.0; approved July 16, 2024).

PP3_Moderate

REVEL 0.938

PP4

Detected in a patient with PAH deficiency (373 μmol/L Phe). Patients with BH4 cofactor deficiency were excluded by BH4 loading. PMID: 28982351

PM1

Missense substitution of residues important in cofactor binding of PAH: Ser250

PM2_Supporting

Absent from gnomAD v4

PM3

Detected in trans by parental testing with a missense variant of unknown significance p.Arg53His (PMID: 28982351) 0.25 points

PS3

the levels of mutant PAH proteins decreased significantly compared to the wild type control, in both E. coli and HEK293T cells. The lower expression in mutant groups indicated that PAH protein expression was impaired by variants. Exact numbers or % of wt were not reported.

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 RT-qPCR. The mutant PAH protein levels were determined by SDS-PAGE, western blot and ELISA. the levels of mutant PAH proteins decreased significantly compared to the wild type control, in both E. coli and HEK293T cells. The lower expression in mutant groups indicated that PAH protein expression was impaired by variants. In general, all four mutations did not affect the transcription of the PAH gene, however, PAH protein synthesis and/or stability was disturbed. Exact numbers or % of wt were not reported. PubMed:29653233

Curation History

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