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

  • See Evidence submitted by expert panel for details.

CA16020875

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

Met criteria codes 3
PM2 PM3_Very Strong PP4_Moderate
Not Met criteria codes 1
BP7

Evidence Links 0

Expert Panel

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.
Met criteria codes
PM2
The c.843-5T>C variant is absent from population databases including gnomAD, ExAC, 1000 Genomes, and ESP.
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).
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).
Not Met criteria codes
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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