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.994G>A

CA386493486

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: a2fb6cff-f898-4e9b-89ba-a3e9ec9f73f7

HGVS expressions

NM_001354304.2:c.994G>A
NC_000012.12:g.102844407C>T
CM000674.2:g.102844407C>T
NC_000012.11:g.103238185C>T
CM000674.1:g.103238185C>T
NC_000012.10:g.101762315C>T
NG_008690.1:g.78196G>A
NG_008690.2:g.119004G>A
ENST00000553106.6:c.994G>A
ENST00000307000.7:c.979G>A
ENST00000549247.6:n.753G>A
ENST00000551114.2:n.656G>A
ENST00000553106.5:c.994G>A
ENST00000635477.1:n.98G>A
ENST00000635528.1:n.509G>A
NM_000277.1:c.994G>A
NM_000277.2:c.994G>A
NM_001354304.1:c.994G>A
NM_000277.3:c.994G>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PP3 PM2 PM3 PP4_Moderate
Not Met criteria codes 1
PM5

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.994G>A (p.Gly332Arg) variant in PAH is a missense variant predicted to cause substitution of glycine by arginine at amino acid 332. It has been detected in 2 patients with PAH deficiency; one with pathogenic variant c.1162G>A, phase unconfirmed (PMID: 29749107) and the other with pathogenic variant deletion of exon 5 in the PAH gene, phase unconfirmed (PMID: 23942198). This variant has extremely low frequency in gnomAD (MAF=0.00006) in the European (Non-Finnish) population. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PM3, PP3, PP4_moderate.
Met criteria codes
PP3
Predicted deleterious in SIFT, PolyPhen-2, and MutationTaster. REVEL= 0.991
PM2
Variant identified in 1/15430 European (Non-Finnish) alleles in gnomAD. Allele frequency is less than 0.0002.
PM3
Detected with c.1162G>A in 1 patient which was classified as pathogenic in ClinVar. Detected with deletion of exon 5 in the PAH gene in another patient which was classified as pathogenic in ClinVar. Phase unknown.
PP4_Moderate
Detected in 2 patients with PAH deficiency. Phe levels for each patient was >120μmol/L. Disease-causing mutations in PAH, GCH1, PTS, and QDPR were confirmed using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA).
Not Met criteria codes
PM5
No other missense change at an amnio acid residue detected in ClinVar
Approved on: 2023-04-01
Published on: 2023-04-01
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