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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

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Criteria Specification: CSpec Registry PDF

Variant: NM_000277.2(PAH):c.1315+2T>C

CA229429

102588 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance

HGVS expressions

NM_000277.2:c.1315+2T>C
NM_000277.2(PAH):c.1315+2T>C
NC_000012.12:g.102840398A>G
CM000674.2:g.102840398A>G
NC_000012.11:g.103234176A>G
CM000674.1:g.103234176A>G
NC_000012.10:g.101758306A>G
NG_008690.1:g.82205T>C
NG_008690.2:g.123013T>C
NM_000277.1:c.1315+2T>C
NM_001354304.1:c.1315+2T>C
NM_000277.3:c.1315+2T>C
ENST00000307000.7:c.1300+2T>C
ENST00000551114.2:n.977+2T>C
ENST00000553106.5:c.1315+2T>C
ENST00000635477.1:n.419+2T>C
ENST00000635528.1:n.830+2T>C

Likely Pathogenic

Met criteria codes 3
PP4_Moderate PM2 PM3_Strong
Unmet criteria codes 1
PP3

Expert Panel

Evidence Links 2

Evidence submitted by expert panel
PAH VCEP
The c.1315+2T>C variant is at the 3' canonical splice site in the penultimate exon of PAH. It is absent form population databases and has been identified in trans with pathogenic variants in three independent patients (F39del, Y414C, and R261X; PMID: 9452062; 9521426). A defect of BH4 metabolism was excluded as a cause of elevated phenylalanine in all patients. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.
Met criteria codes
PP4_Moderate
Two patients, one in trans with Y414C (mild PKU) and one in trans with R261X (classic PKU. BH4 defect excluded in all patients. PMID: 9521426

PM2
Absent from ExAC and gnomAD.
PM3_Strong
In trans with F39del in a single patient with PKU (PMID: 9452062) and in trans with Y414C (mild PKU) and R261X (classic PKU) (PMID: 9521426)

Unmet criteria codes
PP3
Human Splicing Finder suggests no impact on splicing. Michiels, 1998 (PMID 9452062) states this leads to termination of the protein at aa 440/453.
Approved on: 2018-12-09
Published on: 2019-08-17
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