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_001354304.2:c.969+6T>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16020907

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d29f0868-cb34-4d3c-a59f-54e065913844

Approved on: 2020-07-09

Published on: 2022-06-28

HGVS expressions

NM_001354304.2:c.969+6T>C

NC_000012.12:g.102846889A>G

CM000674.2:g.102846889A>G

NC_000012.11:g.103240667A>G

CM000674.1:g.103240667A>G

NC_000012.10:g.101764797A>G

NG_008690.1:g.75714T>C

NG_008690.2:g.116522T>C

ENST00000553106.6:c.969+6T>C

ENST00000307000.7:c.954+6T>C

ENST00000549247.6:n.728+6T>C

ENST00000551114.2:n.631+6T>C

ENST00000553106.5:c.969+6T>C

ENST00000635477.1:n.74-2458T>C

ENST00000635528.1:n.484+6T>C

NM_000277.1:c.969+6T>C

NM_000277.2:c.969+6T>C

NM_001354304.1:c.969+6T>C

NM_000277.3:c.969+6T>C

Uncertain Significance

PM2 PM3_Supporting PP4 PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.969+6T>C variant in PAH is absent from population databases (PM2). It has been observed in at least one mild PKU patient (PMID: 24941924; PP4). The patient is compound heterozygous with pathogenic variant c.1066‐11G>A (ClinVar 607; PM3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP4.

PM2

The c.969+6T>C variant is absent from population databases including gnomAD, ExAC, 1000 Genomes, and ESP.

PM3_Supporting

One patient has been reported (PMID: 24941924) compound heterozygous for c.969 +6T>C and c.1066‐11G>A (ClinVar 607 Pathogenic, reviewed by VCEP). Confirmation of trans phase was not reported.

PP4

One patient has been reported in PMID: 24941924 with mild PKU with Phe between 300–600 μM. Exclusion of BH4 deficiency was not reported.

PP3

MaxEntScan predicts alteration of the WT Donor site, most probably affecting splicing (9.49 > 5.94=> -37.41%). SpliceAI: Splice-Altering (0.57). TraP Score 0.914 (>99.9%). The nucleotide is highly conserved (PhyloP score 2.49).

Curation History

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