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]

Link to SEPIO compliant JSON-LD document

CA6748883

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0fa6b404-a938-4150-bbca-e4162108d153

HGVS expressions

NM_000277.1:c.674C>T

NC_000012.12:g.102855168G>A

CM000674.2:g.102855168G>A

NC_000012.11:g.103248946G>A

CM000674.1:g.103248946G>A

NC_000012.10:g.101773076G>A

NG_008690.1:g.67435C>T

NG_008690.2:g.108243C>T

NM_000277.2:c.674C>T

NM_001354304.1:c.674C>T

NM_000277.3:c.674C>T

NM_001354304.2:c.674C>T

ENST00000307000.7:c.659C>T

ENST00000549111.5:n.770C>T

ENST00000553106.5:c.674C>T

Likely Pathogenic

PP4_Moderate PP3 PM2 PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.674C>T (p.Pro225Leu) variant in PAH has been reported in 2 individuals with PKU (BH4 deficiency excluded (PMID: 21307867). This variant has extremely low frequency in gnomAD MAF=0.000008800. Computational evidence support a deleterious effect. The p.Pro225Thr variant is interpreted as pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3.

PP4_Moderate

PMID 21307867: This study enrolled 203 Japanese residents with a serum phenylalanine level higher than 0.18mM, absence of of neurologic deterioration on a low phenylalanine diet, analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine. Listed in Table 2, phe level not specified

PubMed:31332730

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.967

PM2

extremely low frequency in gnomAD MAF=0.000008800

PM5

p.P225T Pathogenic, p.P225A/R/L no assertion

Approved on: 2020-03-08

Published on: 2020-03-08

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