NM_000277.3:c.189_190dup

CA913184978

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 59b3f077-64b5-45e9-98c0-411996f356ad

Approved on: 2019-04-04

Published on: 2019-08-16

HGVS expressions

NM_000277.3:c.189_190dup
NC_000012.12:g.102894898_102894899dup
CM000674.2:g.102894898_102894899dup
NC_000012.11:g.103288676_103288677dup
CM000674.1:g.103288676_103288677dup
NC_000012.10:g.101812806_101812807dup
NG_008690.1:g.27705_27706dup
NG_008690.2:g.68513_68514dup
NM_000277.1:c.189_190dup
NM_000277.2:c.189_190dup
NM_001354304.1:c.189_190dup
ENST00000307000.7:c.174_175dup
ENST00000546844.1:c.189_190dup
ENST00000548677.2:n.276_277dup
ENST00000548928.1:n.111_112dup
ENST00000549111.5:n.285_286dup
ENST00000550978.6:n.173_174dup
ENST00000551337.5:c.189_190dup
ENST00000551988.5:n.278_279dup
ENST00000553106.5:c.189_190dup
ENST00000635500.1:n.157_158dup

Pathogenic

• Met criteria codes: PM2 PVS1 PP4_Moderate

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.189_190dupTGAC variant in PAH has been previously reported as a single heterozygous variant in a 2.5 year old Chinese proband with PKU, with a second mutation not detected; exact plasma Phe levels were not given, but said to be >20mg/dL and BH4 deficiency was formally excluded by urinary pterin analysis and blood neopterin dihydropteridine reductase assays (PMID: 23271928; PMID: 25863075) (PP4_Moderate). The variant is a frameshift variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate.

Met criteria codes

• PM2: It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).
• PVS1: The variant is a frameshift variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1).
• PP4_Moderate: The c.189_190dupTGAC variant in PAH has been previously reported as a single heterozygous variant in a 2.5 year old Chinese proband with PKU, with a second mutation not detected; exact plasma Phe levels were not given, but said to be >20mg/dL and BH4 deficiency was formally excluded by urinary pterin analysis and blood neopterin dihydropteridine reductase assays (PMID: 23271928; PMID: 25863075) (PP4_Moderate).