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.611A>G (p.Tyr204Cys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229653

590 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 533dfef9-f4fd-434d-8d70-23d08956adf3

Approved on: 2021-03-26

Published on: 2021-03-26

HGVS expressions

NM_000277.3:c.611A>G

NM_000277.3(PAH):c.611A>G (p.Tyr204Cys)

NC_000012.12:g.102855231T>C

CM000674.2:g.102855231T>C

NC_000012.11:g.103249009T>C

CM000674.1:g.103249009T>C

NC_000012.10:g.101773139T>C

NG_008690.1:g.67372A>G

NG_008690.2:g.108180A>G

ENST00000307000.7:c.596A>G

ENST00000553106.5:c.611A>G

NM_000277.1:c.611A>G

NM_000277.2:c.611A>G

NM_001354304.1:c.611A>G

NM_001354304.2:c.611A>G

Pathogenic

PM3_Very Strong PP4_Moderate PP3 PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.611A>G (p.Tyr204Cys) variant in PAH has been reported in multiple individuals with Classic PKU and MHP (BH4 deficiency excluded). (PMID: 15503242). This variant has a MAF (0.00016) in gnomAD. This variant creates a fully active, novel 5 ́ donor splice site which results in an aberrantly spliced mRNA with a 96-nt deletion at the 3 ́-end of exon 6 PMID: 8990021 (aka Ex6-96A>G). Multiple lines of computational evidence support a deleterious effect. This variant was detected in trans with multiple pathogenic variants including: p.R111* (2); c.442-1G>A; p.R158W; p.L255S; p.P281L; p.K363Nfs*37; p.V399V; p.R408W; p.R241C (2); p.R243Q; p.R261Q (2); p.S349A; p.R413P; p.A434D (2) (PMID: 26322415). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3_very-strong, PP3.

PM3_Very Strong

Detected in trans with R111* (2) c.442-1G>A R158W L255S P281L K363Nfs*37 V399V R408W R241C (2) R243Q R261Q (2) S349A R413P A434D (2) PMID: 26322415 >4 points

PP4_Moderate

Detected in multiple patients with classical PKU and MHP. Urinary pterin analysis and DHPR assay excluded 6-pyruvoyl- tetrahydropterin synthase (PTPS) deficiencies. PMID: 15503242

PP3

Predicted deleterious in SIFT (D), PolyPhen2 (P), Mutation Taster (A), REVEL=0.782

PM2

MAF = 0.00016 in gnomAD

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.