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

CA229521

102655 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

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

• Met criteria codes: PM3 PM2 PS2 PP3 PP4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

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.

Met criteria codes

• 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).