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
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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

PP3 PP4_Moderate PM2 PM3_Very Strong

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.

PP3

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

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

PM2

MAF = 0.00016 in gnomAD

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

Curation History

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