NM_001354304.2:c.690_691insG

CA16020841

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: effe9fc1-41ac-418a-84bb-15deca118a02

Approved on: 2020-10-15

Published on: 2020-10-15

HGVS expressions

NM_001354304.2:c.690_691insG
NM_000277.1:c.690_691insG
NM_000277.2:c.690_691insG
NM_001354304.1:c.690_691insG
NM_000277.3:c.690_691insG
ENST00000307000.7:c.675_676insG
ENST00000549111.5:n.786_787insG
ENST00000553106.5:c.690_691insG
NC_000012.12:g.102855151_102855152insC
CM000674.2:g.102855151_102855152insC
NC_000012.11:g.103248929_103248930insC
CM000674.1:g.103248929_103248930insC
NC_000012.10:g.101773059_101773060insC
NG_008690.1:g.67451_67452insG
NG_008690.2:g.108259_108260insG

Pathogenic

• Met criteria codes: PM2 PP4 PVS1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.690_691insG (p.Ser231ValfsTer?) variant in PAH was reported in one patient with Hyperphenylalaninemia (PMID: 28982351). This variant is absent from controls in population databases. This is a frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. 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

• PM2: This variant is absent from controls in gnomAD and ExAC.
• PP4: Observed in a patient with HPA (Phe > 120 µmol/L). Patients with BH4 cofactor deficiency were ruled out using urinary pterin analysis. There is no mention of DHPR being assessed. PMID: 28982351
• PVS1: This is a frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts. Loss of function is a known mechanism of disease: 175 pathogenic null variants reported in Clinvar across 13 different exons, 22 of which are in exon 6.