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(PAH):c.755G>A (p.Arg252Gln)

Curation Version - 1.0
Curation History
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CA229743

102824 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ab854b7c-19a6-4553-ac95-af437437cddf

Approved on: 2018-08-10

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.755G>A

NM_000277.1(PAH):c.755G>A (p.Arg252Gln)

NC_000012.12:g.102852902C>T

CM000674.2:g.102852902C>T

NC_000012.11:g.103246680C>T

CM000674.1:g.103246680C>T

NC_000012.10:g.101770810C>T

NG_008690.1:g.69701G>A

NG_008690.2:g.110509G>A

NM_000277.2:c.755G>A

NM_001354304.1:c.755G>A

NM_000277.3:c.755G>A

ENST00000307000.7:c.740G>A

ENST00000549247.6:n.514G>A

ENST00000553106.5:c.755G>A

Pathogenic

PS3 PP3 PM3 PM2 PP4_Moderate

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: ; PP3: tools predict damaging; PS3: BioPKU 3% enzyme activity; 3.8% residual activity (PMID:24401910); PM3: Detected in trans with p.Pro407fs (PMID:7833954); PP4_Moderate: Detected in 2 patients with classic PKU (Phe>1.5mM). BH4 deficiency excluded (PMID:7833954; PMID:9634518). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate).

PS3

BioPKU 3% enzyme activity; 3.8% residual activity

Figure 1 listed as 3.8% residual activity PubMed:24401910

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3

Detected in trans with p.Pro407fs

In Table 1, in trans with p.Pro407fs PubMed:7833954

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4_Moderate

Detected in 2 patients with classic PKU (Phe>1.5mM). BH4 deficiency excluded

R252Q detected in 2 patients with classic PKU. 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

In Table 1, listed it in trans with p.Pro407fs in a patient with typical PKU (Phe>1.5mM) PubMed:7833954

Curation History

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