The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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
UUID: d9c83133-49d7-48ae-af5f-702bc7606dad

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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