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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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

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

Pathogenic

PM2 PVS1 PM3_Supporting PP4

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

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.

PM2

The variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP.

PVS1

The Gln336Ter nonsense variant occurs in exon 10 of 13 and is predicted to result in NMD.

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.

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.

Approved on: 2022-06-12

Published on: 2022-06-12

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