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CA251545

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 424fcc27-3ba4-4f62-ac78-76b5991ae696

HGVS expressions

NM_001354304.2:c.914_1199+1del
NC_000012.12:g.102843648_102846953del
CM000674.2:g.102843648_102846953del
NC_000012.11:g.103237426_103240731del
CM000674.1:g.103237426_103240731del
NC_000012.10:g.101761556_101764861del
NG_008690.2:g.116461_119766del
ENST00000553106.6:c.914_1199+1del
ENST00000307000.7:c.899_1184+1del
ENST00000549247.6:n.673_958+1del
ENST00000551114.2:n.576_861+1del
ENST00000553106.5:c.914_1199+1del
ENST00000635477.1:n.74-2519_303+1del
ENST00000635528.1:n.429_714+1del
NM_000277.2:c.914_1199+1del
NM_001354304.1:c.914_1199+1del
NM_000277.3:c.914_1199+1del

Likely Pathogenic

Met criteria codes 4
PP4 PM3 PM2 PVS1_Strong

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The g.~6.7kbdel (p.Ex9_11del; c.914_1199+1del; CA251545) in PAH is a large deletion involving exons 9, 10, and 11. The deletion removed exons 9-11 but spared exon 12 in long-range PCR (see PMID: 10472529). This region is critical to protein function, as exons 9 and 10 form part of the PAH catalytic domain, and include key amino acid residues. Therefore, this is a multi-exon deletion that disrupts the reading frame and is NOT predicted to undergo NMD, which truncates/alters a critical region for protein function. Thus, PVS1_Strong is applied. It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in one case with mild PKU (per abnormal blood Phe levels; BH4 deficiency does not appear to have been formally excluded) (PP4), in confirmed trans with the p.E390G variant (Likely Pathogenic per PAH VCEP) (PMID: 10472529) (PM3). Classification: Likely Pathogenic Supporting Criteria: PVS1_Strong; PM2; PM3; PP4
Met criteria codes
PP4
It has been previously reported in one case with mild PKU (per abnormal blood Phe levels; BH4 deficiency does not appear to have been formally excluded) (PP4), in confirmed trans with the p.E390G variant (Likely Pathogenic per PAH VCEP) (PMID: 10472529) (PM3).
PM3
It has been previously reported in one case with mild PKU (per abnormal blood Phe levels; BH4 deficiency does not appear to have been formally excluded) (PP4), in confirmed trans with the p.E390G variant (Likely Pathogenic per PAH VCEP) (PMID: 10472529) (PM3).
PM2
It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).
PVS1_Strong
The c.914_1199+1del involves exons 9, 10, and 11. The deletion removed exons 9-11 but spared exon 12 in long-range PCR (see PMID: 10472529). This region is critical to protein function, as exons 9 and 10 form part of the PAH catalytic domain, and include key amino acid residues. Therefore, this is a multi-exon deletion that disrupts the reading frame and is NOT predicted to undergo NMD, which truncates/alters a critical region for protein function. Thus, PVS1_Strong is applied.
Approved on: 2021-07-25
Published on: 2021-09-19
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