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Variant: NM_000277.3(PAH):c.1199+5G>T

CA229388

102560 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 8d2661b2-c64e-40c5-bc24-b99c7f547416

HGVS expressions

NM_000277.3:c.1199+5G>T
NM_000277.3(PAH):c.1199+5G>T
NC_000012.12:g.102843641C>A
CM000674.2:g.102843641C>A
NC_000012.11:g.103237419C>A
CM000674.1:g.103237419C>A
NC_000012.10:g.101761549C>A
NG_008690.1:g.78962G>T
NG_008690.2:g.119770G>T
NM_000277.1:c.1199+5G>T
NM_000277.2:c.1199+5G>T
NM_001354304.1:c.1199+5G>T
NM_001354304.2:c.1199+5G>T
ENST00000307000.7:c.1184+5G>T
ENST00000549247.6:n.958+5G>T
ENST00000551114.2:n.861+5G>T
ENST00000553106.5:c.1199+5G>T
ENST00000635477.1:n.303+5G>T
ENST00000635528.1:n.714+5G>T

Likely Pathogenic

Met criteria codes 4
PM3 PM2 PP3 PP4

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The intronic variant c.1199+5G>T has been reported in two compound heterozygous probands (Akal, 2019) with Asp338Tyr (ClinVar 102468, Pathogenic) and Ala403Val (ClinVar 92731, Pathogenic). This variant is absent from population databases including ExAC, gnomAD, 1000G, and ESP and computational predictors agree that there is alteration of the WT Donor site, most probably affecting splicing. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4.
Met criteria codes
PM3
Akal 2019 described two compound heterozygous patients harboring c.1199+5G>T as well as Asp338Tyr (ClinVar 102468, Pathogenic) and Ala403Val (ClinVar 92731, Pathogenic; reviewed by VCEP) respectively. Confirmation of trans phase was not reported.
PM2
The variant is absent from population databases including ExAC, gnomAD, 1000G, and ESP.
PP3
HSF (94.42 > 84.72=> -10.27%), MaxEntscan (9.16 > 5.22=> -43.01%), and SplicAI (0.59) agree that there is alteration of the WT Donor site, most probably affecting splicing.
PP4
Two Mild HPA patients (Phe 6-10mg / dl) were reported by Akal in 2019. Exclusion of BH4 deficiency was not reported.

Approved on: 2020-09-12
Published on: 2020-09-12
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