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_000277.3(PAH):c.122T>C (p.Leu41Pro)

CA229408

102573 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 03580416-1048-4c5f-b2f2-112c77d4b7dd

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000277.3:c.122T>C

NM_000277.3(PAH):c.122T>C (p.Leu41Pro)

NC_000012.12:g.102912837A>G

CM000674.2:g.102912837A>G

NC_000012.11:g.103306615A>G

CM000674.1:g.103306615A>G

NC_000012.10:g.101830745A>G

NG_008690.1:g.9766T>C

NG_008690.2:g.50574T>C

ENST00000553106.6:c.122T>C

ENST00000307000.7:c.107T>C

ENST00000546844.1:c.122T>C

ENST00000548677.2:n.209T>C

ENST00000548928.1:n.44T>C

ENST00000549111.5:n.218T>C

ENST00000550978.6:c.106T>C

ENST00000551337.5:c.122T>C

ENST00000551988.5:n.211T>C

ENST00000553106.5:c.122T>C

ENST00000635500.1:n.90T>C

NM_000277.1:c.122T>C

NM_000277.2:c.122T>C

NM_001354304.1:c.122T>C

NM_001354304.2:c.122T>C

Likely Pathogenic

PP4 PM2_Supporting PP3_Moderate PM3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The PAH variant c.122T>C (p.Leu41Pro) was found in one patient with mild PKU (serum phenylalanine levels between 600 and 1,200 μmol/liter) (PP4) with the pathogenic variant c.728G>A (p.Arg243Gln) (CinVar ID: 591) (PMID: 10679941), and in a patient with moderate/mild PKU with the pathogenic variant c.838G>A (p.Glu280Lys) (CinVar ID: 580) (PMID: 22841515) PM3 (Points total = 1). This variant is absent in the gnomAD, ExAC, and PAGE population databases (PM2_Supporting). The variant is predicted to be damaging by REVEL (REVEL score 0.868) (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for PAH deficiency. PAH-specific ACMG/AMP criteria applied: PM2_Supporting, PM3, PP3_Moderate, PP4.

PP4

The PAH variant c.122T>C (p.Leu41Pro) was found in one patient with mild PKU (serum phenylalanine levels between 600 and 1,200 μmol/liter) (PMID: 10679941), and in a patient with moderate/mild PKU (PMID: 22841515). However, none of these studies rule out BH4 cofactor deficiency.

PM2_Supporting

This variant is absent in the gnomAD, ExAC, and PAGE population databases.

PP3_Moderate

In silico modeling predictions for this variant disagree. This variant is predicted to be tolerated by SIFT, possibly damaging by Polyphen 2-HVAR and disease-causing by Mutation Taster. REVEL 0.868

PM3

The c.122T>C (p.Leu41Pro) variant was detected with the pathogenic variants c.728G>A (p.Arg243Gln) (CinVar ID: 591) (PMID: 10679941), and c.838G>A (p.Glu280Lys) (CinVar ID: 580) (PMID: 22841515) PM3 (Points total = 1) .

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