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.122T>C (p.Leu41Pro)

Curation Version - 1.0
Curation History
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CA229408

102573 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

Approved on: 2019-12-22

Published on: 2019-12-22

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

Uncertain Significance

PP4 PM2 PM3

PP3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

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) 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. 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. In summary, this variant meets the criteria to be classified as uncertain significance (insufficient evidence for PAH). PAH-specific ACMG/AMP criteria applied: PM2, PM3, and 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.

PubMed:22841515

PubMed:10679941

PM2

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

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) .

PP3

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.

Curation History

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