NM_001354304.2:c.912+1G>C

CA16020894

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: f74343ee-09ba-4e2b-937f-b06c6f9727c5

Approved on: 2020-07-24

Published on: 2020-07-24

HGVS expressions

NM_001354304.2:c.912+1G>C
NM_000277.1:c.912+1G>C
NM_000277.2:c.912+1G>C
NM_001354304.1:c.912+1G>C
NM_000277.3:c.912+1G>C
ENST00000307000.7:c.897+1G>C
ENST00000549247.6:n.671+1G>C
ENST00000551114.2:n.574+1G>C
ENST00000553106.5:c.912+1G>C
ENST00000635477.1:n.73+1G>C
NC_000012.12:g.102851686C>G
CM000674.2:g.102851686C>G
NC_000012.11:g.103245464C>G
CM000674.1:g.103245464C>G
NC_000012.10:g.101769594C>G
NG_008690.1:g.70917G>C
NG_008690.2:g.111725G>C

Pathogenic

• Met criteria codes: PVS1 PM2 PP4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.912+1G>C variant in PAH is a canonical splice donor in which exon skipping disrupts the reading frame and is predicted to undergo nonsense mediated-decay. This variant was reported in 2 patients with PKU (PMID 25550961, 31332730). Additionally, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, and PP4.

Met criteria codes

• PVS1: Canonical +1 splice donor, exon skipping disrupts reading frame, predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 8 out of 13 coding exons (8 out of total exons). Variant removes more than 10% of transcript (5.2% of transcript.)
• PM2: Absent from 1000G, ESP, and gnomAD.
• PP4: Reported in a patient with PKU. Patients were subjected to tetrahydrobiopterin load and Phe tolerance tests, to rule out tetrahydrobiopterin deficiency (PMID 25550961). This variant was also documented in a patient with PKU or hyperphenylalaninemia in a Russia cohort, specificity of phenotype not provided (PMID 31332730). It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant in either patient.