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.662A>G (p.Glu221Gly)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229677

609 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: dfac2ff9-0b20-422d-a189-df2e2ff04e34

Approved on: 2020-05-22

Published on: 2020-05-22

HGVS expressions

NM_000277.2:c.662A>G

NM_000277.2(PAH):c.662A>G (p.Glu221Gly)

NM_000277.1:c.662A>G

NM_001354304.1:c.662A>G

NM_000277.3:c.662A>G

NM_001354304.2:c.662A>G

ENST00000307000.7:c.647A>G

ENST00000549111.5:n.758A>G

ENST00000553106.5:c.662A>G

NC_000012.12:g.102855180T>C

CM000674.2:g.102855180T>C

NC_000012.11:g.103248958T>C

CM000674.1:g.103248958T>C

NC_000012.10:g.101773088T>C

NG_008690.1:g.67423A>G

NG_008690.2:g.108231A>G

Likely Pathogenic

PP4_Moderate PP3 PM3 PM2

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.662A>G (p.Glu221Gly) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded) and MHP. (PMID: 1679030 8860005 10947211). It was detected in trans with pathogenic variant L48S and in the homozygous state. This variant has extremely low frequency in ExAC (0.00001) and gnomAD (0.000004064). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.

PP4_Moderate

E221G seen in 2 unrelated PKU patients. Cofactor deficiency was ruled out in 1 patient. Upgraded per ClinGen PAHEP. PMID: 1679030 PMID: 8860005 PMID: 10947211

6 independent Costa Rican PKU families with at least 1 affected child, all classified as having classical PKU per Guttler criteria. E221G was found in 1 patient/allele. PubMed:8860005

Turkish patient with classic phenylketonuria, The Leu48Ser amino acid substitution and the Glu221Gly substitutions were found. The Glu221Gly mutation has only been detected within patient E1 and his father. Patient was tested for cofactor deficiency within 1 month of life. PubMed:1679030

PP3

Predicted deleterious by SIFT, Polyphen, MutationTaster

PM3

E221G found in trans with L48S, which is Pathogenic in ClinVar

PubMed:10947211

Glu221Gly found in trans with Leu48Ser in a Turkish patient with PKU. L48S is classified as Pathogenic in ClinVar (VarID 608). PubMed:1679030

PM2

Extremely low frequency in ExAC (0.00001) and gnomAD (0.000004064)

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.