Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229388

102560 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8d2661b2-c64e-40c5-bc24-b99c7f547416

Approved on: 2020-09-12

Published on: 2020-09-12

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

PM2 PM3 PP3 PP4

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

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.

PM2

The variant is absent from population databases including ExAC, gnomAD, 1000G, and ESP.

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.

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.

PubMed:10408782

Curation History

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