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.231T>G (p.Tyr77Ter)

CA229493

102635 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 566c47a8-afb9-4069-998d-80ae462e7113

Approved on: 2023-10-15

Published on: 2023-10-15

HGVS expressions

NM_000277.3:c.231T>G

NM_000277.3(PAH):c.231T>G (p.Tyr77Ter)

NC_000012.12:g.102894856A>C

CM000674.2:g.102894856A>C

NC_000012.11:g.103288634A>C

CM000674.1:g.103288634A>C

NC_000012.10:g.101812764A>C

NG_008690.1:g.27747T>G

NG_008690.2:g.68555T>G

ENST00000553106.6:c.231T>G

ENST00000307000.7:c.216T>G

ENST00000546844.1:c.231T>G

ENST00000548677.2:n.318T>G

ENST00000548928.1:n.153T>G

ENST00000549111.5:n.327T>G

ENST00000550978.6:c.215T>G

ENST00000551337.5:c.231T>G

ENST00000551988.5:n.320T>G

ENST00000553106.5:c.231T>G

NM_000277.1:c.231T>G

NM_000277.2:c.231T>G

NM_001354304.1:c.231T>G

NM_001354304.2:c.231T>G

Pathogenic

PM2_Supporting PP4_Moderate PVS1 PM3

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.231T>G (p.Tyr77Ter) 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, and ESP, and is present at an extremely low allele frequency (MAF < 0.0002) in the 1000 Genomes (PM2_supporting). The variant has been previously reported in a patient with PKU (plasma Phe level not specified) and BH4 deficiency excluded (PMID: 9860305; PMID: 21307867) (PP4_Moderate); the patient’s genotype was not specified. It has also been noted (PMID: 28982351) in a patient with mild PKU (plasma Phe 720 uM) and BH4 deficiency excluded (PP4_Moderate), who harbored it in trans with the p.Asp101Asn (Likely Pathogenic in ClinVar, ID 553851) and p.Gly247Arg (Likely Pathogenic in ClinVar, ID 102816) alleles (PM3). In summary, this variant meets criteria to be classified as for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PM3, PP4_Moderate.

PM2_Supporting

The variant is absent from population databases including gnomAD, ExAC, and ESP, and is present at an extremely low allele frequency (MAF < 0.0002) in the 1000 Genomes (PM2).

PP4_Moderate

The variant has been noted (PMID: 28982351) in a patient with mild PKU (plasma Phe 720 uM) and BH4 deficiency excluded (PP4_Moderate).

PVS1

The NM_000277.3(PAH):c.231T>G (p.Tyr77Ter) 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).

PM3

It has also been noted (PMID: 28982351) in a patient with mild PKU (plasma Phe 720 uM) and BH4 deficiency excluded (PP4_Moderate), who harbored it in trans with the p.Asp101Asn (Likely Pathogenic in ClinVar, ID 553851) and p.Gly247Arg (Likely Pathogenic in ClinVar, ID 102816) alleles (PM3).

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