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]

Link to SEPIO compliant JSON-LD document

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

CA229669

102769 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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 PM3_Supporting PP4

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.

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.

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

Approved on: 2020-10-30

Published on: 2020-10-30

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