The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

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

CA229662

102763 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: b1d613a1-7e11-43ff-ad0d-9e0dca6c4fbc
Approved on: 2020-04-13
Published on: 2020-04-13

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
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Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PM2 PM3_Very Strong PP4_Moderate PVS1
Not Met criteria codes 2
PP3 PS3

Evidence Links 1

Expert Panel

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
Met criteria codes
PM2
not found
PM3_Very Strong
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).
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).

PVS1
Null variant (nonsense) in a gene where LOF is a known mechanism of disease
Not Met criteria codes
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
Curation History
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