Variant: NM_001354304.2:c.353-2059_353-1160del

CA916084428

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: cd8344f7-1e0b-4cb1-be82-ce00e55665a0

Approved on: 2020-12-25

Published on: 2022-03-11

HGVS expressions

NM_001354304.2:c.353-2059_353-1160del
NC_000012.12:g.102878710_102879609del
CM000674.2:g.102878710_102879609del
NC_000012.11:g.103272488_103273387del
CM000674.1:g.103272488_103273387del
NC_000012.10:g.101796618_101797517del
NG_008690.1:g.42994_43893del
NG_008690.2:g.83802_84701del
ENST00000553106.6:c.353-2059_353-1160del
ENST00000307000.7:c.338-2059_338-1160del
ENST00000549111.5:n.449-2059_449-1160del
ENST00000550978.6:n.337-2059_337-1160del
ENST00000551337.5:c.353-2059_353-1160del
ENST00000551988.5:n.442-2059_442-1160del
ENST00000553106.5:c.353-2059_353-1160del
NM_000277.1:c.353-2059_353-1160del
NM_000277.2:c.353-2059_353-1160del
NM_001354304.1:c.353-2059_353-1160del
NM_000277.3:c.353-2059_353-1160del

Uncertain Significance

• Met criteria codes: PP4_Moderate PM2

• Not Met criteria codes: PVS1 PM3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The p.Intron3del899 (g.103272488_103273387del) variant is an 899bp deletion in Intron 3 of PAH. It has been previously reported as a variant of “uncertain clinical significance” in patient with PKU (plasma Phe levels not provided in paper; BH4 deficiency excluded by sequencing of the genes in the BH4 cofactor metabolism pathway) (PP4_Moderate), who also harbored a deletion in exon 5 (g.103272488_103273386del, leading to a frameshift at His170) and the c.994G>A (p.G322R) missense variant (unclassified/VUS) (PMID: 23942198). It is absent from ethnically diverse control databases, including gnomAD (structural variant version, gnomAD SVs v2.1) (PM2). Classification: VUS Supporting criteria: PM2; PP4_Moderate

Met criteria codes

• PP4_Moderate: It has been previously reported as a variant of “uncertain clinical significance” in patient with PKU (plasma Phe levels not provided in paper; BH4 deficiency excluded by sequencing of the genes in the BH4 cofactor metabolism pathway) (PP4_Moderate), who also harbored a deletion in exon 5 (g.103272488_103273386del, leading to a frameshift at His170) and the c.994G>A (p.G322R) missense variant (unclassified/VUS) (PMID: 23942198).
• PM2: It is absent from ethnically diverse control databases, including gnomAD (structural variant version, gnomAD SVs v2.1) (PM2).

Not Met criteria codes

• PVS1: The p.Intron3del899 (g.103272488_103273387del) variant is an 899bp deletion in Intron 3 of PAH.
• PM3: Phase not reported for 3 variants in PMID: 23942198