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.754C>T (p.Arg252Trp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA251529

584 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3641e358-76ec-4492-b57b-e0456cc8d34b

Approved on: 2018-08-13

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.754C>T

NM_000277.1(PAH):c.754C>T (p.Arg252Trp)

NC_000012.12:g.102852903G>A

CM000674.2:g.102852903G>A

NC_000012.11:g.103246681G>A

CM000674.1:g.103246681G>A

NC_000012.10:g.101770811G>A

NG_008690.1:g.69700C>T

NG_008690.2:g.110508C>T

NM_000277.2:c.754C>T

NM_001354304.1:c.754C>T

NM_000277.3:c.754C>T

ENST00000307000.7:c.739C>T

ENST00000549247.6:n.513C>T

ENST00000553106.5:c.754C>T

Pathogenic

PM2 PS3 PM3 PP3 PP4

PM5

Evidence Links 5

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: gnomAD MAF: 0.00006; PP3: tools predict damaging ; PS3: 1% residual activity (PMID:25596310; PMID:17935162); PP4: Detection of codon 252arg>trp in a patient with PAH deficiency (PMID:2574153); PM3: Detected with IVS10-11G>A, R261Q, IVS12+1, R68S (all P/LP). (PMID:18299955; PMID:11524738). 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, PP4, PM3).

PM2

gnomAD MAF: 0.00006

PS3

1% residual activity

0.9% activity in Table S4 (HGMD). PubMed:25596310

In Table 1 listed it as 1% residual activity. PubMed:17935162

PM3

Detected with IVS10-11G>A, R261Q, IVS12+1, R68S (all P/LP).

Patient genotype: IVS10-11G>A (VarID 607, Pathogenic) + R252W PubMed:18299955

Patient 10 genotype: R261Q (VarID 582 P/LP) /R252W. Patient 28: IVS12nt1 (VarID 576, P) /R252W. Patient 42: R252W/R68S (VarID 92738, P/LP). PubMed:11524738

PP3

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

PP4

Detection of codon 252arg>trp in a patient with PAH deficiency

we carried out the systematic sequence analysis of exon 7 in 20 unrelated PAH-deficient kindreds of Mediterranean ancestry. This procedure resulted in the detection of two novel missense mutations whose location and nature (CG to CA and CG to TG) were consistent with the accidental deamination of a 5-methylcytosine in a CpG doublet (codon 261arg----gln and codon 252arg----trp). PubMed:2574153

PM5

p.Arg252Gln pathogenic

Curation History

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