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.561G>C (p.Trp187Cys)

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Curation History
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CA229626

102737 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1c0ae89b-f759-4875-b648-8f454598bad8

Approved on: 2021-10-31

Published on: 2022-06-12

HGVS expressions

NM_000277.3:c.561G>C

NM_000277.3(PAH):c.561G>C (p.Trp187Cys)

NC_000012.12:g.102855281C>G

CM000674.2:g.102855281C>G

NC_000012.11:g.103249059C>G

CM000674.1:g.103249059C>G

NC_000012.10:g.101773189C>G

NG_008690.1:g.67322G>C

NG_008690.2:g.108130G>C

ENST00000553106.6:c.561G>C

ENST00000307000.7:c.546G>C

ENST00000549111.5:n.657G>C

ENST00000551988.5:n.582G>C

ENST00000553106.5:c.561G>C

NM_000277.1:c.561G>C

NM_000277.2:c.561G>C

NM_001354304.1:c.561G>C

NM_001354304.2:c.561G>C

Likely Pathogenic

PM3_Supporting PP4_Moderate PS3_Supporting PP3 PM2

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.561G>C (p.Trp187Cys) variant in PAH has been reported in a Japanese PKU patient (BH4 deficiency ruled out, genotype not reported; 21307867), and 2 Brazilian siblings with PKU (PMID: 30829006). It was detected with the pathogenic variant p.Val388Met in the siblings. PAH activity for this variant was 1% compared to wild type in a COS cell expression system (PMID: 9860305). This variant is absent in population databases, and predicted deleterious in multiple lines of computational evidence. In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4_moderate, PS3_supporting, PM2, PM3_supporting, PP3.

PM3_Supporting

detected with V388M (P by 6 submitters) in Brazilian siblings, parental analysis not reported PMID: 30829006. Genotype not reported for Japanese patient.

PP4_Moderate

Reported in a Japanese PKU patient (analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine PMID: 21307867) and 2 Brazilian siblings with PKU (moderate and mild) PMID: 30829006

PS3_Supporting

PAH activity for W187C was 1% compared to wild type in COS cell expression system. PMID: 9860305 This PMID approved for PS3-supp on PAH VCEP call 2/25/22

PP3

Predicted deleterious in SIFT, Polyphen-2, MutationTaster, REVEL=0.94

PM2

absent in gnomAD

PM5

p.Trp187Arg is LP by PAH VCEP.

Curation History

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