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_000277.3(PAH):c.353-6T>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229521

102655 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0e052ab5-f2b3-4f5f-ad80-c21f5686cd92

Approved on: 2020-07-25

Published on: 2020-07-25

HGVS expressions

NM_000277.3:c.353-6T>A

NM_000277.3(PAH):c.353-6T>A

NM_000277.1:c.353-6T>A

NM_000277.2:c.353-6T>A

NM_001354304.1:c.353-6T>A

NM_001354304.2:c.353-6T>A

ENST00000307000.7:c.338-6T>A

ENST00000549111.5:n.449-6T>A

ENST00000550978.6:n.337-6T>A

ENST00000551337.5:c.353-6T>A

ENST00000551988.5:n.442-6T>A

ENST00000553106.5:c.353-6T>A

NC_000012.12:g.102877556A>T

CM000674.2:g.102877556A>T

NC_000012.11:g.103271334A>T

CM000674.1:g.103271334A>T

NC_000012.10:g.101795464A>T

NG_008690.1:g.45047T>A

NG_008690.2:g.85855T>A

Pathogenic

PM3 PM2 PS2 PP3 PP4

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

(PAH):c.353-6T>A is an intronic variant predicted to be splice altering/deleterious by multiple lines of in silico data. This variant was reported in trans with the pathogenic variant p.Tyr414Cys in a patient with mild PKU in a Norwegian cohort (PMID 8807331). This variant was confirmed to be de novo by parental sequencing (PMID 8807331). (PAH):c.353-6T>A is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS2, PM2, PM3, PP3, and PP4.

PM3

Detected in trans with pathogenic variant p. Tyr414Cys in a patient with mild PKU. Parental analysis was done (PMID 27121329).

PM2

Absent in GnomAD database.

PS2

IVS3-6T>A was not inherited, whereas Mendelian transmission was confirmed for the other mutations (by DNA sequencing of relevant parents, results not shown). IVS3-6T>A had arisen on the paternal haplotype 5.8 chromosome. The results of the paternity testing were compatible with arising as a de novo mutation. Trans with pathogenic variant p. Tyr414Cys (PMID 8807331)

PP3

Splicing altering event predicted by Splicing AI (0.87) and dbsSNV predicts deleterious effect (0.99) and RF (0.84). Greater than 99th percentile in TraP for predicted deleterious score (0.501).

PP4

This variant was reported in a compound heterozygous patient with mild PKU in a Norwegian cohort. Detected in trans with pathogenic variant Tyr414Cys (PMID: 8807331).

Curation History

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