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]

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CA16020875

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 35d1ac45-c501-4a98-ad14-ddf8fa49ba76

Approved on: 2020-09-12

Published on: 2020-09-12

HGVS expressions

NM_001354304.2:c.843-5T>C

NM_000277.1:c.843-5T>C

NM_000277.2:c.843-5T>C

NM_001354304.1:c.843-5T>C

NM_000277.3:c.843-5T>C

ENST00000307000.7:c.828-5T>C

ENST00000549247.6:n.602-5T>C

ENST00000551114.2:n.500T>C

ENST00000553106.5:c.843-5T>C

ENST00000635477.1:n.4-5T>C

NC_000012.12:g.102851761A>G

CM000674.2:g.102851761A>G

NC_000012.11:g.103245539A>G

CM000674.1:g.103245539A>G

NC_000012.10:g.101769669A>G

NG_008690.1:g.70842T>C

NG_008690.2:g.111650T>C

Pathogenic

PM2 PP4_Moderate PM3_Very Strong

BP7

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.843-5T>C variant in PAH is absent from population databases (PM2). It has been observed in several classic PKU patients with BH4 deficiency excluded (PMID: 24048906 and PMID: 22526846; PP4). has been reported in at least 6 homozygous patients and 12 compound heterozygous patients harboring 7 additional Pathogenic/Likely Pathogenic variants (PMIDs: 31924462, 29892150, 30159852, 24048906, 22526846, PM3. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_VeryStrong, PP4_moderate.

PM2

The c.843-5T>C variant is absent from population databases including gnomAD, ExAC, 1000 Genomes, and ESP.

PP4_Moderate

At least 18 patients have been reported with the c.843-5T>C variant, at least four of whom had Phe levels >1000 uM and exclusion of BH4 deficiency (PMID: 24048906 and PMID: 22526846).

PM3_Very Strong

The c.843-5T>C variant has been reported in at least 6 homozygous patients and 12 compound heterozygous patients harboring 7 additional Pathogenic/Likely Pathogenic variants: P281L (ClinVar 589, Likely Pathogenic), c.168+5G>C (ClinVar 102606, Pathogenic), R176X (ClinVar 102723, Pathogenic), Y386C (ClinVar 102538, Likely Pathogenic), A300S (ClinVar 102528, Likely Pathogenic), R261Q (ClinVar 582, Pathogenic), R408W (ClinVar 557, Pathogenic).

BP7

HSF and MaxEntScan predict no significant impact on splicing signals, however the nucleotide is highly conserved across vertebrates (PhyloP score of 6.007).

Curation History

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