Variant: NM_000277.3(PAH):c.970-1G>C

CA242744496

595611 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 249bece1-35e2-4ced-9c05-3156e7796a54

Approved on: 2023-03-16

Published on: 2023-03-16

HGVS expressions

NM_000277.3:c.970-1G>C
NM_000277.3(PAH):c.970-1G>C
NC_000012.12:g.102844432C>G
CM000674.2:g.102844432C>G
NC_000012.11:g.103238210C>G
CM000674.1:g.103238210C>G
NC_000012.10:g.101762340C>G
NG_008690.1:g.78171G>C
NG_008690.2:g.118979G>C
ENST00000553106.6:c.970-1G>C
ENST00000307000.7:c.955-1G>C
ENST00000549247.6:n.729-1G>C
ENST00000551114.2:n.632-1G>C
ENST00000553106.5:c.970-1G>C
ENST00000635477.1:n.74-1G>C
ENST00000635528.1:n.485-1G>C
NM_000277.1:c.970-1G>C
NM_000277.2:c.970-1G>C
NM_001354304.1:c.970-1G>C
NM_001354304.2:c.970-1G>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PVS1_Strong PP4_Moderate PM2

• Not Met criteria codes: PM3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.970-1G>C variant in PAH occurs within the canonical splice acceptor site of intron 9. This is predicted to cause in-frame skipping of exon 10. It has been detected in a patient with PAH deficiency with second allele not reported (PMID: 31332730). The variant is absent in population databases. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH deficiency based on this ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PP4_moderate, PVS1_strong

Met criteria codes

• PVS1_Strong: This is a canonical -1 splice site variant where exon skipping does not disrupts reading frame and where altered region is critical to protein function. Number of pathogenic non-nonsense variants in skipped exon: 33
• PP4_Moderate: Detected in 1 patients with PAH deficiency. The Phe level was ≥120μmol/L in the patients. For the search of rare variants, the Next Generation Sequencing user panel Ampliseq™, covering the DNA cod- ing sequence, exon boundaries, and also partially covering 5′ and 3′untranslated regions of PAH, PTS, GCH1, PCBD1, QDPR, SPR and DNAJC12 genes, was developed using Ion AmpliSeq™software PMID: 31332730
• PM2: Absent from controls in gnomAD, ExAC, 1000 Genomes, or ESP

Not Met criteria codes

• PM3: Second allele not reported