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.161T>C (p.Leu54Ser)

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Curation History
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CA229448

102602 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bfb0df54-1132-4767-9598-0268a4485799

Approved on: 2020-07-23

Published on: 2021-02-12

HGVS expressions

NM_000277.3:c.161T>C

NM_000277.3(PAH):c.161T>C (p.Leu54Ser)

NC_000012.12:g.102912798A>G

CM000674.2:g.102912798A>G

NC_000012.11:g.103306576A>G

CM000674.1:g.103306576A>G

NC_000012.10:g.101830706A>G

NG_008690.1:g.9805T>C

NG_008690.2:g.50613T>C

NM_000277.1:c.161T>C

NM_000277.2:c.161T>C

NM_001354304.1:c.161T>C

NM_001354304.2:c.161T>C

ENST00000307000.7:c.146T>C

ENST00000546844.1:c.161T>C

ENST00000548677.2:n.248T>C

ENST00000548928.1:n.83T>C

ENST00000549111.5:n.257T>C

ENST00000550978.6:n.145T>C

ENST00000551337.5:c.161T>C

ENST00000551988.5:n.250T>C

ENST00000553106.5:c.161T>C

ENST00000635500.1:n.129T>C

Likely Pathogenic

PP4_Moderate PP3 PM2 PM3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.161T>C (p.Leu54Ser) variant in PAH is a missense variant that is predicted to be deleterious in multiple lines of computational evidence. This variant was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring the dihydropteridine reductase activity (PMID: 27121329). This variant was detected in trans with pathogenic variant c.912+1G>A. It was found in extremely low frequency in gnomAD (MAF=0.00006). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4 moderate, PM3, and PP3.

PP4_Moderate

Reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity. PMID: 27121329

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster, REVEL=0.876

PM2

Extremely low frequency in gnomAD (MAF=0.00006)

PM3

Detected in trans with pathogenic variant c.912+1G>A (6 submitters) Segregation analysis was done. PMID: 27121329

Curation History

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