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

Curation Version - 1.0
Curation History
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CA229654

102758 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

Approved on: 2020-05-08

Published on: 2020-05-08

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

PP4_Moderate PM2 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

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).

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).

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

Curation History

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