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_000277.1(PAH):c.612T>G (p.Tyr204Ter)

CA229654

102758 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 368fcdd7-ba64-404b-82a6-30ab165d389d

HGVS expressions

NM_000277.1:c.612T>G

NM_000277.1(PAH):c.612T>G (p.Tyr204Ter)

NC_000012.12:g.102855230A>C

CM000674.2:g.102855230A>C

NC_000012.11:g.103249008A>C

CM000674.1:g.103249008A>C

NC_000012.10:g.101773138A>C

NG_008690.1:g.67373T>G

NG_008690.2:g.108181T>G

NM_000277.2:c.612T>G

NM_001354304.1:c.612T>G

NM_000277.3:c.612T>G

NM_001354304.2:c.612T>G

ENST00000307000.7:c.597T>G

ENST00000549111.5:n.708T>G

ENST00000553106.5:c.612T>G

Pathogenic

PM2 PP4_Moderate PVS1 PM3_Strong

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.612T>G (p.Tyr204Ter) variant in PAH is a null variant (nonsense variant) in exon 6 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequency in ethnically diverse control databases, with gnomAD AF 0.00000398 (<0.002, the PAH-specific cutoff) (PM2). It has been reported as a heterozygous variant in at least four PKU cases, with known pathogenic variants in at least two cases (PM3_Strong): with a Sicilian PKU case with BH4 deficiency excluded (PMID: 8268925) (PP4_Moderate); in a German PKU case (PMID: 10394930); in one Spanish case with the pathogenic (per PAH VCEP) p.R176L variant (PMID: 10234516); and in one family (2 affected siblings) and 2 additional mild PKU patients with the pathogenic (per PAH VCEP) p.R68S variant (PMID: 23514811). It has also been reported Pathogenic by three labs in ClinVar (variation ID 102758). Classification: Pathogenic Supporting criteria: PVS1, PM2; PM3_Strong; PP4_Moderate

PM2

It is present at extremely low frequency in ethnically diverse control databases, with gnomAD AF 0.00000398 (<0.002, the PAH-specific cutoff) (PM2).

PP4_Moderate

It has been reported as a heterozygous variant in at least four PKU cases, in trans with known pathogenic variants in at least two cases (PM3_Strong): a Sicilian PKU case with BH4 deficiency excluded (PMID: 8268925) (PP4_Moderate); in a German PKU case (PMID: 10394930); one Spanish case with the pathogenic (per PAH VCEP) p.R176L variant (PMID: 10234516); and in one family (2 affected siblings) in trans with the pathogenic (per PAH VCEP) p.R68S variant (PMID: 23514811)It has also been reported Pathogenic by three labs in ClinVar (variation ID 102758).

PVS1

Null variant (nonsense) in a gene where LOF is a known mechanism of disease

PM3_Strong

It has been reported as a heterozygous variant in at least four PKU cases, with known pathogenic variants in at least two cases (PM3_Strong): one Spanish case with the pathogenic (per PAH VCEP) p.R176L variant (PMID: 10234516); and in one family (2 affected siblings) and 2 additional patients with the pathogenic (per PAH VCEP) p.R68S variant (PMID: 23514811)

In trans with p.P211T (ClinVar, LP) PubMed:23690520

Approved on: 2020-05-08

Published on: 2020-05-08

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.