Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • No ClinVar Id was directly found from the curated document

Variant: NM_001354304.2:c.604G>A

CA16020827

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 320632f8-4070-4fff-a5d8-b3ae0f9c3c0d

HGVS expressions

NM_001354304.2:c.604G>A
NC_000012.12:g.102855238C>T
CM000674.2:g.102855238C>T
NC_000012.11:g.103249016C>T
CM000674.1:g.103249016C>T
NC_000012.10:g.101773146C>T
NG_008690.1:g.67365G>A
NG_008690.2:g.108173G>A
ENST00000553106.6:c.604G>A
ENST00000307000.7:c.589G>A
ENST00000549111.5:n.700G>A
ENST00000553106.5:c.604G>A
NM_000277.1:c.604G>A
NM_000277.2:c.604G>A
NM_001354304.1:c.604G>A
NM_000277.3:c.604G>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PM3_Supporting PP3 PM2 PP4_Moderate
Not Met criteria codes 1
PS3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.604G>A (p.Ala202Thr) variant in PAH has been reported in at least one individual with classic PKU with BH4 deficiency excluded. In this patient it was observed without confirmed phase with c.728G>A (p.Arg243Gln), which is classified as Pathogenic in ClinVar (Variation ID 591). In-vitro functional studies are unavailable. This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PM3_Supporting, PP4_Moderate.
Met criteria codes
PM3_Supporting
Observed with c.728G>A (p.Arg243Gln) (classified as Pathogenic in ClinVar Variation ID 591), with unconfirmed phase.
PP3
Damaging in SIFT, Probably damaging in PolyPhen 2, Disease causing in MutationTaster, REVEL=0.936
PM2
Absent from controls in ExAC, gnomAD, 1000 Genomes, and ESP
PP4_Moderate
Observed in one patient with classic PKU with BH4 deficiency excluded via urinary pterin analyses and DHPR assay (PMID: 18985011).
Not Met criteria codes
PS3
No available functional study.
Approved on: 2023-03-16
Published on: 2023-03-16
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