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

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA114368

627 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

Approved on: 2018-12-10

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:c.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

Uncertain Significance

PP4_Moderate PP3 PM2

Evidence Links 2

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 in a Pakistani patient with non-PKU hyperphenylalaninemia (BH4 deficiency excluded) (PP4_Moderate; PMID: 8364546, 9634518) This variant is absent from 1000G and ESP, and has an extremely low frequency in ExAC and gnomAD (MAF=0.00016). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.846. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3.

PP4_Moderate

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

L98S reported in a functionally hemizygous patient (same patient as Guldberg 1993?). In all patients, hyperphenylalaninemia had been detected by national mass screening programs, and PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism. PubMed:9634518

The results of the DGGE analysis stated that the patient is homozygous for a mutation in exon 3, and that both parents are heterozygous carriers. Direct sequencing of exon 3 identified a T—C transition at position 515 in the PAH cDNA. This mutation changes codon 98 from TTG to TCG, resulting in the substitution of Leu with Ser. She was detected by neonatal screening presenting with a serum phenylalanine value of 300 /umol/L. Phenylalanine levels have persistently been between 225 and 770 /umol/L on a normal dietary intake of phenylalanine with only a single value above 600 /umol/l. PubMed:8364546

PP3

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

PM2

Absent from 1000G, ESP. Extremely low frequency in ExAC, gnomAD (MAF=0.00016)

Curation History

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