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.799C>T (p.Gln267Ter)

CA16020861

665198 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3519e57f-b52e-4dd0-9b9f-c1eb8a2cb319

HGVS expressions

NM_000277.3:c.799C>T

NM_000277.3(PAH):c.799C>T (p.Gln267Ter)

NM_000277.1:c.799C>T

NM_000277.2:c.799C>T

NM_001354304.1:c.799C>T

NM_001354304.2:c.799C>T

ENST00000307000.7:c.784C>T

ENST00000549247.6:n.558C>T

ENST00000553106.5:c.799C>T

NC_000012.12:g.102852858G>A

CM000674.2:g.102852858G>A

NC_000012.11:g.103246636G>A

CM000674.1:g.103246636G>A

NC_000012.10:g.101770766G>A

NG_008690.1:g.69745C>T

NG_008690.2:g.110553C>T

Pathogenic

PP4_Moderate PM2 PVS1 PM3_Strong

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The PAH variant c.799C>T (p.Gln267Ter) is a null variant (stop gain) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. The mRNA transcript is predicted to undergo NMD. The variant c.799C>T (p.Gln267Ter) was reported in trans with the pathogenic PAH variant c.442-1G>A (ClinVar ID: 594) in a Chinese patient with classic PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID: 26322415). The PAH variant c.799C>T (p.Gln267Ter) was also reported in trans with the pathogenic PAH variant IVS10‐11G>A (ClinVar ID: 607) in a Brazilian patient with classic PKU (PMID: 18798839) PM3_Strong (2.0). The variant c.799C>T (p.Gln267Ter) is absent from the gnomAD, ExAC, PAGE, and ESP population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Strong, PVS1, PP4-moderate.

PP4_Moderate

The variant c.799C>T (p.Gln267Ter) was reported in a Chinese patient with classic PKU (Phe levels >20 mg/dl). All patients in this study had a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID: 26322415)

PubMed:26322415

PM2

The PAH variant Q267* is absent from the gnomAD, ExAC, PAGE, and ESP population databases.

PVS1

According to Franklin, the variant p.Q267* is a null variant (stop gain). The loss of function in the PAH gene is a mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. The mRNA transcript is predicted to undergo NMD, not located in the last exon or last 50bp of the preliminary exon. Coding exon number 7 out of 13 coding exons.

PM3_Strong

The PAH variant c.799C>T (p.Gln267Ter) was reported in a Brazilian patient in trans with the pathogenic variant IVS10‐11G>A (ClinVar ID: 607) (PMID: 18798839), and in a Chinese patient in trans with the pathogenic variant, c.442-1G>A (ClinVar ID: 594) (PMID: 26322415). Both patients were classified as having classic PKU. PM3_Strong (2.0)

PubMed:18798839

Approved on: 2020-05-09

Published on: 2020-05-09

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