Variant: NM_000277.3(PAH):c.1196_1199del (p.Val399fs)

CA229378

102551 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: cf002636-011c-4f50-b2ac-390b69cabf90

Approved on: 2022-10-14

Published on: 2022-10-14

HGVS expressions

NM_000277.3:c.1196_1199del
NM_000277.3(PAH):c.1196_1199del (p.Val399fs)
NC_000012.12:g.102843649_102843652del
CM000674.2:g.102843649_102843652del
NC_000012.11:g.103237427_103237430del
CM000674.1:g.103237427_103237430del
NC_000012.10:g.101761557_101761560del
NG_008690.1:g.78954_78957del
NG_008690.2:g.119762_119765del
ENST00000553106.6:c.1196_1199del
ENST00000307000.7:c.1181_1184del
ENST00000549247.6:n.955_958del
ENST00000551114.2:n.858_861del
ENST00000553106.5:c.1196_1199del
ENST00000635477.1:n.300_303del
ENST00000635528.1:n.711_714del
NM_000277.1:c.1196_1199del
NM_000277.2:c.1196_1199del
NM_001354304.1:c.1196_1199del
NM_001354304.2:c.1196_1199del

Likely Pathogenic

• Met criteria codes: PVS1_Strong PP4 PM3 PM2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.3(PAH):c.1196_1199del (p.Val399Glyfs*52) is a frameshift variant in exon 11 of 13 that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay. Exon 13 is considered a critical region because it (along with Exon 12) forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (PVS1_Strong). At least one patient (Case 154 in PMID: 8807331) with this variant had classical PKU with a serum phenylalanine level of 2131 μmol/L (above the >120 μmol/L requirement). Exclusion of a defect of BH4 cofactor metabolism was not reported (PP4). Case 154 (PMID: 8807331) is compound heterozygous for c.196_1199del and Arg408Trp (ClinVar 577, classified Pathogenic by the PAH VCEP; PM3). This variant is absent from gnomAD v2.1.1 (PM2). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive phenylketonuria based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1_strong, PP4, PM3, PM2. (PAH VCEP specifications version 1).

Met criteria codes

• PVS1_Strong: The c.1196_1199del (p.Val399Glyfs*52) variant in PAH is a frameshift variant in exon 11 of 13 that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay, due to the resulting premature stop codon in exon 13, and therefore remove 0.4% of the protein. Exon 13 is considered a critical region because it (along with Exon 12) forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (PVS1_Strong).
• PP4: At least one patient (Case 154 in PMID: 8807331) with this variant had classical PKU with a serum phenylalanine level of 2131 umol/l (above the >120 μmol/L requirement). Exclusion of a defect of BH4 cofactor metabolism was not reported (PP4).
• PM3: Case 154 (PMID: 8807331) is compound heterozygous for c.196_1199del and Arg408Trp (ClinVar 577, classified Pathogenic by the PAH VCEP; PM3).
• PM2: This variant is absent from gnomAD v2.1.1 (PM2).