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.1027T>G (p.Tyr343Asp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229280

102476 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fc07dc52-569c-4021-87b5-e54628c440f9

Approved on: 2020-06-01

Published on: 2020-06-01

HGVS expressions

NM_000277.3:c.1027T>G

NM_000277.3(PAH):c.1027T>G (p.Tyr343Asp)

NC_000012.12:g.102844374A>C

CM000674.2:g.102844374A>C

NC_000012.11:g.103238152A>C

CM000674.1:g.103238152A>C

NC_000012.10:g.101762282A>C

NG_008690.1:g.78229T>G

NG_008690.2:g.119037T>G

NM_000277.1:c.1027T>G

NM_000277.2:c.1027T>G

NM_001354304.1:c.1027T>G

NM_001354304.2:c.1027T>G

ENST00000307000.7:c.1012T>G

ENST00000549247.6:n.786T>G

ENST00000551114.2:n.689T>G

ENST00000553106.5:c.1027T>G

ENST00000635477.1:n.131T>G

ENST00000635528.1:n.542T>G

Likely Pathogenic

PP4_Moderate PM3 PM2 PP3

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.1027T>G (p.Tyr343Asp) variant in PAH has been reported in 1 individual with mild PKU (BH4 deficiency excluded) detected in trans with p.S349P (PMID: 27121329). This variant is absent in population databases. Computational evidence supports 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

Seen in a patient with mPKU, not BH4 responsive. The current cutoff value for Phe is 120 μM. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity. PMID: 27121329

Seen in a patient with mPKU, not BH4 responsive. PubMed:27121329

PM3

Seen in trans with S349P, pathogenic/likely pathogenic in Clinvar (Var ID: 615). Segregation analysis was done to rule out the presence of large genomic rearrangements. PMID: 27121329

Seen in trans with S349P, pathogenic/likely pathogenic in Clinvar (Var ID: 615) PubMed:27121329

PM2

absent from controls.

PP3

Predicted deleterious by MutationTaster, SIFT, Polyphen2.

PM5

Y343C classified as likely pathogenic

Curation History

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