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.226G>T (p.Glu76Ter)

CA16020752

495789 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 848a19e1-be21-4d94-b0f8-1c6fd86f2e1b

Approved on: 2023-10-15

Published on: 2023-10-15

HGVS expressions

NM_000277.3:c.226G>T

NM_000277.3(PAH):c.226G>T (p.Glu76Ter)

NC_000012.12:g.102894861C>A

CM000674.2:g.102894861C>A

NC_000012.11:g.103288639C>A

CM000674.1:g.103288639C>A

NC_000012.10:g.101812769C>A

NG_008690.1:g.27742G>T

NG_008690.2:g.68550G>T

ENST00000553106.6:c.226G>T

ENST00000307000.7:c.211G>T

ENST00000546844.1:c.226G>T

ENST00000548677.2:n.313G>T

ENST00000548928.1:n.148G>T

ENST00000549111.5:n.322G>T

ENST00000550978.6:c.210G>T

ENST00000551337.5:c.226G>T

ENST00000551988.5:n.315G>T

ENST00000553106.5:c.226G>T

NM_000277.1:c.226G>T

NM_000277.2:c.226G>T

NM_001354304.1:c.226G>T

NM_001354304.2:c.226G>T

Pathogenic

PVS1 PM2_Supporting PP4

BP2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.3(PAH):c.226G>T (p.Glu76Ter) is a nonsense variant in exon 3/13 of PAH, and is predicted to result in PTC with removal of >10% of the protein and NMD (PVS1). The variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP (PM2_supporting). The variant has been previously reported in a patient with classic PKU (plasma Phe >1200 uM) (PMID: 17096675) with BH4 deficiency not noted to have been formally excluded (PP4), in cis with the c.1089delG variant (ClinVar Pathogenic, see ID 102518). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4.

PVS1

nonsense variant in exon 3/13 of PAH, , and is predicted to result in PTC with removal of >10% of the protein and NMD (PVS1).

PM2_Supporting

The variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP (PM2).

PP4

Complex allele p.E76X* + c.1089delG has been previously reported in a patient with classic PKU (plasma Phe >1200 uM) (PMID: 17096675) with BH4 deficiency not noted to have been formally excluded (PP4)

BP2

The variant has been previously reported in a patient with classic PKU (plasma Phe >1200 uM) (PMID: 17096675) with BH4 deficiency not noted to have been formally excluded (PP4), in cis with the c.1089delG variant (ClinVar Pathogenic, see ID 102518) and no further details regarding the patient’s genotype appear to be included

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