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_000277.2(PAH):c.650G>A (p.Cys217Tyr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229674

102772 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1ca809f3-bf55-4607-8218-009893a28356

Approved on: 2018-12-10

Published on: 2019-04-05

HGVS expressions

NM_000277.2:c.650G>A

NM_000277.2(PAH):c.650G>A (p.Cys217Tyr)

NC_000012.12:g.102855192C>T

CM000674.2:g.102855192C>T

NC_000012.11:g.103248970C>T

CM000674.1:g.103248970C>T

NC_000012.10:g.101773100C>T

NG_008690.1:g.67411G>A

NG_008690.2:g.108219G>A

NM_000277.1:c.650G>A

NM_001354304.1:c.650G>A

NM_000277.3:c.650G>A

ENST00000307000.7:c.635G>A

ENST00000549111.5:n.746G>A

ENST00000553106.5:c.650G>A

Uncertain Significance

PP4_Moderate PP3 PM2

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.650G>A (p.Cys217Tyr) variant in PAH was reported in 1 Japanese PKU patient. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. (PMID: 21307867). This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.982. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3.

PP4_Moderate

C217Y seen in 1 Japanese PKU patient. DHPR activity, biopterin and/or pteridine analysis performed. PMID: 21307867

This study enrolled 203 Japanese residents with a serum phenylalanine level higher than 0.18mM. PAH deficiency was diagnosed at the participating institutions on the basis of absence 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. C217Y was detected on 1 allele. PubMed:21307867

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.982

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM5

2 other variants at this codon, no clinical significance in ClinVar

Curation History

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