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.1089G>T (p.Lys363Asn)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229334

102517 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9a6918e9-715e-4432-9857-2279bf43050a

Approved on: 2021-02-26

Published on: 2021-02-26

HGVS expressions

NM_000277.3:c.1089G>T

NM_000277.3(PAH):c.1089G>T (p.Lys363Asn)

NC_000012.12:g.102843756C>A

CM000674.2:g.102843756C>A

NC_000012.11:g.103237534C>A

CM000674.1:g.103237534C>A

NC_000012.10:g.101761664C>A

NG_008690.1:g.78847G>T

NG_008690.2:g.119655G>T

ENST00000307000.7:c.1074G>T

ENST00000553106.5:c.1089G>T

NM_000277.1:c.1089G>T

NM_000277.2:c.1089G>T

NM_001354304.1:c.1089G>T

NM_001354304.2:c.1089G>T

Uncertain Significance

BP4 PP4_Moderate PM2 PM3_Strong

PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1089G>T (p.Lys363Asn) variant in PAH has been reported in 3 patients with mild HPA and mild PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out. It was detected in trans with pathogenic variants Phe55Leufs*6 (PMID: 27121329) and c.442-1G>A (PMID: 29316886). This variant is absent in population databases. However, multiple lines of computation evidence suggest no impact on the PAH protein. In summary, computational evidence conflicts with case level evidence and is therefore classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, BP4.

BP4

Tolerated in SIFT, Benign in PolyPhen2, Neutral in MutationTaster. REVEL=0.429.

PP4_Moderate

Detected in a Spanish patient with mild HPA (no treatment). A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. PMID: 27121329. Detected in 2 Chinese patients with mild HP (240 umol/L); mild PKU (1004 umol/L)

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PM3_Strong

Detected in trans with c.442-1G>A (P, 3 submitters); IVS12-2A>G (not in ClinVar) PMID: 29316886; Phe55Leufs*6 (P, 4 submitters) PMID: 27121329 2 points=strong

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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