NM_001354304.2:c.1199+1G>T

CA16020960

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 3f40cd3f-bf5e-4a61-91a4-1037fa0fc65a

Approved on: 2022-12-09

Published on: 2022-12-09

HGVS expressions

NM_001354304.2:c.1199+1G>T
NC_000012.12:g.102843645C>A
CM000674.2:g.102843645C>A
NC_000012.11:g.103237423C>A
CM000674.1:g.103237423C>A
NC_000012.10:g.101761553C>A
NG_008690.1:g.78958G>T
NG_008690.2:g.119766G>T
ENST00000553106.6:c.1199+1G>T
ENST00000307000.7:c.1184+1G>T
ENST00000549247.6:n.958+1G>T
ENST00000551114.2:n.861+1G>T
ENST00000553106.5:c.1199+1G>T
ENST00000635477.1:n.303+1G>T
ENST00000635528.1:n.714+1G>T
NM_000277.1:c.1199+1G>T
NM_000277.2:c.1199+1G>T
NM_001354304.1:c.1199+1G>T
NM_000277.3:c.1199+1G>T

Pathogenic

• Met criteria codes: PVS1 PM3_Supporting PP4 PM2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1199+1G>T variant in exon 11 of PAH disrupts a canonical splice donor site. It is predicted to cause skipping of biologically-relevant-exon 11/13, resulting in a frameshift leading to nonsense mediated decay (PVS1). At least one patient (PMID: 31623983) with this variant had classic PKU with a serum phenylalanine level >1200uM (PP4). This patient is compound heterozygous for c.1199+1G>T and Arg408Trp (ClinVar 577, classified Pathogenic by the PAH VCEP) without confirmation of phase (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive phenylketonuria based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PP4, PM3, PM2. (PAH VCEP specifications version 1; date of approval xx/xx/xxxx).

Met criteria codes

• PVS1: The c.1199+1G>T variant in exon 11 of PAH disrupts a canonical splice donor site. It is predicted to cause skipping of biologically-relevant-exon 11/13, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PM3_Supporting: One patient in PMID: 31623983 is compound heterozygous for c.1199+1G>T and Arg408Trp (ClinVar 577, classified Pathogenic by the PAH VCEP), however, investigation of trans phase was not reported (PM3_supporting).
• PP4: At least one patient (PMID: 31623983) with this variant had classic PKU with a serum phenylalanine level >1200uM (above the >120 μmol/L requirement). Exclusion of a defect of BH4 cofactor metabolism was not reported (PP4).
• PM2: This variant is absent from gnomAD v2.1.1 (PM2).