Evidence Repository
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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Variant: NM_000277.3(PAH):c.1006C>T (p.Gln336Ter)

CA229264

102465 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: bbf26ac8-3611-47c0-9a87-22fed4d3be26
Approved on: 2022-06-12
Published on: 2022-06-12

HGVS expressions

NM_000277.3:c.1006C>T
NM_000277.3(PAH):c.1006C>T (p.Gln336Ter)
NC_000012.12:g.102844395G>A
CM000674.2:g.102844395G>A
NC_000012.11:g.103238173G>A
CM000674.1:g.103238173G>A
NC_000012.10:g.101762303G>A
NG_008690.1:g.78208C>T
NG_008690.2:g.119016C>T
ENST00000553106.6:c.1006C>T
ENST00000307000.7:c.991C>T
ENST00000549247.6:n.765C>T
ENST00000551114.2:n.668C>T
ENST00000553106.5:c.1006C>T
ENST00000635477.1:n.110C>T
ENST00000635528.1:n.521C>T
NM_000277.1:c.1006C>T
NM_000277.2:c.1006C>T
NM_001354304.1:c.1006C>T
NM_001354304.2:c.1006C>T
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Pathogenic

Met criteria codes 4
PVS1 PM2 PP4 PM3_Supporting

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.1006C>T (p.Gln336Ter) nonsense variant occurs in exon 10 of 13 and is predicted to result in NMD. It absent from population databases, including gnomAD. It has been reported in at least one patient with cPKU (PMID: 23764561), compound heterozygous with R408W (ClinVar 577 Pathogenic, reviewed by PAH VCEP). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4.
Met criteria codes
PVS1
The Gln336Ter nonsense variant occurs in exon 10 of 13 and is predicted to result in NMD.
PM2
The variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP.
PP4
Patient 31 of PMID: 23764561 has classic PKU with Phe ≥ 1200 μmol/L. Authors state that patients with BH4 deficiency were excluded but do not say by what method BH4 deficiency was excluded.
PM3_Supporting
Patient 31 of PMID: 23764561 is compound heterozygous for Q336X and R408W (ClinVar 577 Pathogenic, reviewed by PAH VCEP). Confirmation of trans phase not reported.
Curation History
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