Evidence Repository - GenboreeKB

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_001354304.2:c.182A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA386304246

1514901 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d4685748-0588-468c-8d29-601bfd5dda45

Approved on: 2025-07-18

Published on: 2025-07-18

HGVS expressions

NM_001354304.2:c.182A>G

NC_000012.12:g.102894905T>C

CM000674.2:g.102894905T>C

NC_000012.11:g.103288683T>C

CM000674.1:g.103288683T>C

NC_000012.10:g.101812813T>C

NG_008690.1:g.27698A>G

NG_008690.2:g.68506A>G

ENST00000553106.6:c.182A>G

ENST00000307000.7:c.167A>G

ENST00000546844.1:c.182A>G

ENST00000548677.2:n.269A>G

ENST00000548928.1:n.104A>G

ENST00000549111.5:n.278A>G

ENST00000550978.6:c.166A>G

ENST00000551337.5:c.182A>G

ENST00000551988.5:n.271A>G

ENST00000553106.5:c.182A>G

ENST00000635500.1:n.150A>G

NM_000277.1:c.182A>G

NM_000277.2:c.182A>G

NM_001354304.1:c.182A>G

NM_000277.3:c.182A>G

Uncertain Significance

PP4_Moderate PM2_Supporting PM5

PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.3(PAH):c.182A>G (p.Asn61Ser)variant in PAH is a missense variant predicted to cause substitution of asparagine by serine at amino acid 61 (p.Asn61Ser). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) AND normal urine pterins and DHPR activity to exclude a defect of BH4 cofactor metabolism, which is highly specific for Phenylketonuria (PP4_Moderate; PMID:29499199). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 2 different missense variants c.181A>G (p.Asn61Asp) and c.183C>A (p.Asn61Lys) in the same codon have been classified as likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5). Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria VCEP: PP4_moderate, PM2_supporting, PM5 (Version 2.0, 7/16/2024).

PP4_Moderate

At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) AND normal urine pterins and normal DHPR activity to exclude a defect of BH4 cofactor metabolism, which is highly specific for Phenylketonuria (PP4_Moderate; PMID:29499199).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting)

PM5

2 different missense variants c.181A>G (p.Asn61Asp) and c.183C>A (p.Asn61Lys) in the same codon have been classified as likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5).

PP3

The computational predictor REVEL gives a score of 0.597, which is neither above nor below the thresholds predicting a damaging or benign impact on PAH function.

Curation History

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