Variant: NM_000277.3(PAH):c.593_614del (p.Tyr198fs)

CA229639

102747 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 5677a6d7-20db-4d63-b6fa-b69008c476be

Approved on: 2020-07-24

Published on: 2020-07-24

HGVS expressions

NM_000277.3:c.593_614del
NM_000277.3(PAH):c.593_614del (p.Tyr198fs)
NM_000277.1:c.593_614del
NM_000277.2:c.593_614del
NM_001354304.1:c.593_614del
NM_001354304.2:c.593_614del
ENST00000307000.7:c.578_599del
ENST00000549111.5:n.689_710del
ENST00000553106.5:c.593_614del
NC_000012.12:g.102855228_102855249del
CM000674.2:g.102855228_102855249del
NC_000012.11:g.103249006_103249027del
CM000674.1:g.103249006_103249027del
NC_000012.10:g.101773136_101773157del
NG_008690.1:g.67354_67375del
NG_008690.2:g.108162_108183del

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PM3_Very Strong PM2 PP4_Moderate PVS1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.593_614del (p.Tyr198fs) frameshift variant in PAH is predicted to undergo nonsense mediated-decay. This variant was reported in 9 patients with PAH deficiency (PMID 27121329, 26210745, 21871829, 26666653). A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329, 21871829). This variant was detected in trans with 3 pathogenic/LP variants (PMID 27121329) and in 6 patients with pathogenic/LP variants with unknown phasing (PMID 26210745, 21871829, 26666653). This variant is absent in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3 very strong, PM2, and PP4 moderate.

Met criteria codes

• PM3_Very Strong: Detected in trans with pathogenic/LP variants p.Val230Ile (n=2) and p.Ser349Pro (n=1). Segregation analysis was done (PMID 27121329). 6 pathogenic/LP variants with unknown phasing were heterozygous with this variant: c.1241A>G, c.781T>C, c.1315+2T>C, p.R158Q, p.R243X, c.969+1G>A (PMID 26210745, 21871829, 26666653).
• PM2: Absent from gnomAD.
• PP4_Moderate: Reported in 3 patients with PAH deficiency. (mild HPA-NT (2) <360 μmol /1 And CPKU (1) >1200 μmol /1) A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID 27121329). In an Italian cohort, 3 patients with classic PKU were observed (PMID 26210745) and 2 with unspecified PAH deficiency in a Portuguese cohort (PMID 21871829). Diagnosis was confirmed after exclusion of BH4 deficiency by evaluating urinary pterin levels and erythrocyte dihydropteridine reductase activity (PMID 21871829). In a French cohort one patient was identified with classic PKU (cPKU, Phe > 1200 μmol/L) (PMID 26666653).
• PVS1: Frameshift variant predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 6 out of 13 coding exons (6 out of total exons)