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_000277.1(PAH):c.618C>G (p.Tyr206Ter)

CA229662

102763 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b1d613a1-7e11-43ff-ad0d-9e0dca6c4fbc

HGVS expressions

NM_000277.1:c.618C>G

NM_000277.1(PAH):c.618C>G (p.Tyr206Ter)

NC_000012.12:g.102855224G>C

CM000674.2:g.102855224G>C

NC_000012.11:g.103249002G>C

CM000674.1:g.103249002G>C

NC_000012.10:g.101773132G>C

NG_008690.1:g.67379C>G

NG_008690.2:g.108187C>G

NM_000277.2:c.618C>G

NM_001354304.1:c.618C>G

NM_000277.3:c.618C>G

NM_001354304.2:c.618C>G

ENST00000307000.7:c.603C>G

ENST00000549111.5:n.714C>G

ENST00000553106.5:c.618C>G

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PP4_Moderate PM2 PVS1 PM3_Very Strong

PP3 PS3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.618C>G (p.Tyr206Ter) 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 absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been reported in at least six PKU patients (per abnormal blood Phe levels) (PP4), including in trans with pathogenic variants: with R158Q (pathogenic per PAH VCEP) (PMID: 30829006); homozygous in an Indian case with classic PKU (PMID: 24130151); in trans with the known pathogenic (per PAH VCEP) p.R408W variant (PMID: 9452062); in a Chinese PKU case in trans with the known pathogenic (per PAH VCEP) EX6-96A>G variant (PMID: 16256386); and in two Spanish patients, in trans with the pathogenic (per PAH VCEP) Thr380Met and the p.Ala309Val variants, respectively (PMID: 27121329) (PM3_VeryStrong). It has also been reported Likely Pathogenic by one lab in ClinVar (variation ID 102763). Classification: Pathogenic Supporting criteria: PVS1, PM2; PM3_VeryStrong; PP4

PP4_Moderate

It has been reported in at least six PKU patients (per abnormal blood Phe levels) (PP4), including in trans with pathogenic variants: with R158Q (pathogenic per PAH VCEP) (PMID: 30829006); homozygous in an Indian case with classic PKU (PMID: 24130151); in trans with the known pathogenic (per PAH VCEP) p.R408W variant (PMID: 9452062); in a Chinese PKU case in trans with the known pathogenic (per PAH VCEP) EX6-96A>G variant (PMID: 16256386); and in two Spanish patients, in trans with the pathogenic (per PAH VCEP) Thr380Met and the p.Ala309Val variants, respectively (PMID: 27121329) (PM3_VeryStrong). It has also been reported Likely Pathogenic by one lab in ClinVar (variation ID 102763).

Phe>180 uM, BH4 defect was excluded; phenotype and Phe concentration was not specified for c.618C>G variant PubMed:23514811

PM2

not found

PVS1

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

PM3_Very Strong

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS3

0% enzyme activity (BioPKU) PubMed:23514811

Approved on: 2020-04-13

Published on: 2020-04-13

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