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_000277.2(PAH):c.293T>C (p.Leu98Ser)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA114368

627 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fcf34e9b-443b-490c-af8d-a6643cc7dc59

Approved on: 2022-01-14

Published on: 2022-01-14

HGVS expressions

NM_000277.2:c.293T>C

NM_000277.2(PAH):c.293T>C (p.Leu98Ser)

NC_000012.12:g.102894794A>G

CM000674.2:g.102894794A>G

NC_000012.11:g.103288572A>G

CM000674.1:g.103288572A>G

NC_000012.10:g.101812702A>G

NG_008690.1:g.27809T>C

NG_008690.2:g.68617T>C

ENST00000553106.6:c.293T>C

ENST00000307000.7:c.278T>C

ENST00000546844.1:c.293T>C

ENST00000548928.1:n.215T>C

ENST00000549111.5:n.389T>C

ENST00000550978.6:n.277T>C

ENST00000551337.5:c.293T>C

ENST00000551988.5:n.382T>C

ENST00000553106.5:c.293T>C

NM_000277.1:c.293T>C

NM_001354304.1:c.293T>C

NM_000277.3:c.293T>C

NM_001354304.2:c.293T>C

NM_000277.3(PAH):c.293T>C (p.Leu98Ser)

Likely Pathogenic

PM3_Supporting PP4_Moderate PP3 PM2

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.293T>C (p.Leu98Ser) variant in PAH has been reported as homozygous in a Pakistani patient with mild PKU (BH4 deficiency excluded) (PMID: 8364546, 9634518, 26542770) This variant has an extremely low frequency in gnomAD v2.1.1 (MAF=0.0001307). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.846. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3.

PM3_Supporting

Detected as homozygous, confirmed by parental testing PMID: 26542770

PP4_Moderate

Detected in a Pakistani patient with non-PKU hyperphenylalaninemia. BH4 deficiency excluded. ( PMID: 8364546, 9634518) Upgraded per ClinGen PAH EP.

PP3

Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.846.

PM2

Absent from 1000G, ESP. Extremely low frequency in ExAC, gnomAD v2.1.1 (0.0001307)

PM5

L98V is LP by PAH VCEP

Curation History

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