Variant: NM_000277.3(PAH):c.1316-1G>A

CA386492907

635216 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: ee19ff36-b76d-477e-ba35-e3e10dbf495b

Approved on: 2020-04-16

Published on: 2020-04-16

HGVS expressions

NM_000277.3:c.1316-1G>A
NM_000277.3(PAH):c.1316-1G>A
NC_000012.12:g.102839219C>T
CM000674.2:g.102839219C>T
NC_000012.11:g.103232997C>T
CM000674.1:g.103232997C>T
NC_000012.10:g.101757127C>T
NG_008690.1:g.83384G>A
NG_008690.2:g.124192G>A
ENST00000553106.6:c.1316-1G>A
ENST00000307000.7:c.1301-1G>A
ENST00000551114.2:n.978-1G>A
ENST00000553106.5:c.1316-1G>A
ENST00000635477.1:c.420-1G>A
ENST00000635528.1:n.831-1G>A
NM_000277.1:c.1316-1G>A
NM_000277.2:c.1316-1G>A
NM_001354304.1:c.1316-1G>A
NM_001354304.2:c.1316-1G>A

Pathogenic

• Met criteria codes: PP4_Moderate PVS1_Moderate PM2 PM3_Very Strong

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1316-1G>A variant in PAH is a null variant (canonical +/- 1 or 2 splice sites) in a gene where LOF is a known mechanism of disease. It is predicted to result in skipping of coding exon 13, which is a key domain of the enzyme (PVS1_Moderate). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in seven Ugyur probands (PMID: 31355225): three homozygotes with mild PKU; one compound heterozygote with classic PKU in trans with the p.R413P variant (Pathogenic per ClinGen PAH working group); one compound heterozygote with classic PKU in trans with the p.R243Q variant (Pathogenic per ClinGen PAH working group); one compound heterozygote with mild PKU in trans with the p.A300S variant (Pathogenic per ClinGen PAH working group); and one compound heterozygote with mild PKU in trans with the p.E182K (Likely Pathogenic per ClinGen PAH working group) variant (PM3_VeryStrong). (In all cases, phase was confirmed by parental testing.) In all cases, BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate). It is reported pathogenic in Clinvar (ID 625286) by one lab, for PKU; no further information is given.

Met criteria codes

• PP4_Moderate: It has been previously reported in seven Ugyur probands (PMID: 31355225): three homozygotes with mild PKU; one compound heterozygote with classic PKU in trans with the p.R413P variant (Pathogenic per ClinGen PAH working group); one compound heterozygote with classic PKU in trans with the p.R243Q variant (Pathogenic per ClinGen PAH working group); one compound heterozygote with mild PKU in trans with the p.A300S variant (Pathogenic per ClinGen PAH working group); and one compound heterozygote with mild PKU in trans with the p.E182K (Likely Pathogenic per ClinGen PAH working group) variant (PM3_VeryStrong). (In all cases, phase was confirmed by parental testing.) In all cases, BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate).
• PVS1_Moderate: The c.1316-1G>A variant in PAH is a null variant (canonical +/- 1 or 2 splice sites) in a gene where LOF is a known mechanism of disease. It is predicted to result in skipping of coding exon 13, which is a key domain of the enzyme (PVS1_Moderate). Exon 13 encodes 15 amino acids + stop codon = 3.3% of PAH protein length. Along with Exon 12, Exon 13 forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (e.g., positve cooperativity by the substrate, L-Phe, and decreasing PAH activity at low L-Phe concentration) (see PMID: 23457044; PMID: 22005392). Exon 13 contains the non-truncating Likely Pathogenic p.A447P (Likely Pathogenic by ClinGen PAH VCEP) and Pathogenic p.A447D variants (Likely Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 102595; 4 submitters, 2 stars). Thus PVS1_Moderate will be applied for deletion of this exon, e.g., by splice variants.
• PM2: It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).
• PM3_Very Strong: It has been previously reported in seven Ugyur probands (PMID: 31355225): three homozygotes with mild PKU; one compound heterozygote with classic PKU in trans with the p.R413P variant (Pathogenic per ClinGen PAH working group); one compound heterozygote with classic PKU in trans with the p.R243Q variant (Pathogenic per ClinGen PAH working group); one compound heterozygote with mild PKU in trans with the p.A300S variant (Pathogenic per ClinGen PAH working group); and one compound heterozygote with mild PKU in trans with the p.E182K (Likely Pathogenic per ClinGen PAH working group) variant (PM3_VeryStrong).