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.527G>T (p.Arg176Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA114371

631 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ef5918af-b40e-498d-b65d-a5935b878854

Approved on: 2020-10-16

Published on: 2020-10-16

HGVS expressions

NM_000277.3:c.527G>T

NM_000277.3(PAH):c.527G>T (p.Arg176Leu)

NC_000012.12:g.102855315C>A

CM000674.2:g.102855315C>A

NC_000012.11:g.103249093C>A

CM000674.1:g.103249093C>A

NC_000012.10:g.101773223C>A

NG_008690.1:g.67288G>T

NG_008690.2:g.108096G>T

NM_000277.1:c.527G>T

NM_000277.2:c.527G>T

NM_001354304.1:c.527G>T

NM_001354304.2:c.527G>T

ENST00000307000.7:c.512G>T

ENST00000549111.5:n.623G>T

ENST00000551988.5:n.548G>T

ENST00000553106.5:c.527G>T

Pathogenic

PP4_Moderate PS3 PM3_Very Strong

PM2 PM5 PP3

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.527G>T (p.Arg176Leu) variant in PAH was reported in multiple patients with hyperphenylalaninemia and detected with 11 pathogenic variants (PMID: 27121329, 9634518, and 29288420). Experimental studies from two publications have demonstrated this variant to have a deleterious effect (PMID: 17924342 and 30037505). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PS3, and PP4_moderate.

PP4_Moderate

This variant is seen in at least three patients with hyperphenylalaninemia (Phe is between 120-600 µmol/L). In at least one patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity. PMID: 9634518, 29288420, and 27121329

PubMed:27121329

PS3

Experimental studies from two publications have demonstrated that this variant reduced the enzymatic activity of PAH to 35-42%in vitro. PMID: 17924342 and 30037505

Experimental studies have shown that this missense variant reduces the enzymatic activity of PAH to 42% in vitro. PubMed:17924342

Experimental studies in COS cells have shown that this missense variant reduces the enzymatic activity of PAH to 35% and the total PAH protein levels to 80% in vitro. PubMed:30037505

PM3_Very Strong

p.[Arg176Leu];[Phe39del] (n=2), p.[Arg176Leu];[Leu48Ser] (n=2), p.[Arg176Leu];[Tyr277Asp], p.[Arg243*];[Arg176Leu] (n=3), p.[Arg176Leu];[Arg243Gln], p.[Arg176Leu];[Tyr414Cys] (n=3), p.[Arg176Leu];[Glu390Gly], p.[Arg176Leu];[Arg408Trp], p.[Arg176Leu];[Glu280Lys], c.[912G4A];p.[Arg176Leu], p.[Arg176Leu];[Arg261Gln] (n=4). Segregation analysis was done. PMID: 27121329

PubMed:29288420

PubMed:9634518

PM2

MAF from gnomAD is 0.00028. The PM2 threshold set by the PAH Variant Curation Expert Panel (VCEP) is 0.0002.

PM5

R176Q pathogenic by 1 submitter (Invitae); R176P no interpretation in ClinVar. Not applying to this variant since PM5 will be used for evidence with R176Q.

PP3

SIFT, PolyPhen2, and MutationTaster conflict in their prediction. SIFT predicts damaging, PolyPhen2 predicts benign, and MutationTaster predicts polymorphism.

Curation History

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