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]

Variant: NM_000277.3(PAH):c.648C>G (p.Tyr216Ter)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229669

102769 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bef3eb83-0cda-4e62-8d6e-2cee996c411c

Approved on: 2020-10-30

Published on: 2020-10-30

HGVS expressions

NM_000277.3:c.648C>G

NM_000277.3(PAH):c.648C>G (p.Tyr216Ter)

NC_000012.12:g.102855194G>C

CM000674.2:g.102855194G>C

NC_000012.11:g.103248972G>C

CM000674.1:g.103248972G>C

NC_000012.10:g.101773102G>C

NG_008690.1:g.67409C>G

NG_008690.2:g.108217C>G

NM_000277.1:c.648C>G

NM_000277.2:c.648C>G

NM_001354304.1:c.648C>G

NM_001354304.2:c.648C>G

ENST00000307000.7:c.633C>G

ENST00000549111.5:n.744C>G

ENST00000553106.5:c.648C>G

Pathogenic

PM2 PVS1 PP4 PM3_Supporting

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.648C>G (p.Tyr216Ter) variant has been identified in at least one patient with classic PKU (PMID: 26666653). The patient was compound heterozygous with the pathogenic variant Glu280Lys (ClinVar 580). This variant is absent from 1000G, ESP, and gnomAD databases. This variant creates a stop codon in exon 6 of 13 which is predicted to cause NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2, PM3_supporting.

PM2

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

PVS1

The Tyr216Ter nonsense variant creates a stop codon in exon 6 of 13 which is predicted to cause NMD.

PP4

At least one proband with this variant has been described (PMID: 26666653) with the classic PKU phenotype and PHE >1200umol/L. Exclusion of defects in BH4 cofactor metabolism was not reported.

PubMed:26666653

PM3_Supporting

At least one patient has been reported (PMID: 26666653) compound heterozygous for Tyr216Ter and Glu280Lys (ClinVar 580, Pathogenic by multiple submitters). Confirmation of trans phase was not reported.

Curation History

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