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_001354304.1:c.470G>C

CA16020797

619162 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a2d92aa7-5fed-4ba2-be23-93c6b25c50cb

HGVS expressions

NM_001354304.1:c.470G>C

ENST00000553106.6:c.470G>C

ENST00000307000.7:c.455G>C

ENST00000549111.5:n.566G>C

ENST00000551988.5:n.530+10827G>C

ENST00000553106.5:c.470G>C

NM_000277.1:c.470G>C

NM_000277.2:c.470G>C

NM_000277.3:c.470G>C

NM_001354304.2:c.470G>C

NC_000012.12:g.102866635C>G

CM000674.2:g.102866635C>G

NC_000012.11:g.103260413C>G

CM000674.1:g.103260413C>G

NC_000012.10:g.101784543C>G

NG_008690.1:g.55968G>C

NG_008690.2:g.96776G>C

Uncertain Significance

PM2 PM5 PP3

PS3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.470G>C (p.Arg157Thr) variant in PAH has not been reported in an affected patient to our knowledge. The reference in BioPKU (Carter KC, 1998) does not include this variant. The p.R157T mutant is listed as having 5% of wt PAH activity in vitro (BioPKU), but this likely corresponds to the p.R157N variant (PMID: 9450897). The p.Arg157Asn variant at the same amino acid is interpreted as pathogenic in ClinVar (VarID 590772). p.Arg157Thr is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen-2, MutationTaster, and REVEL=0.95. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3.

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM5

R157N is pathogenic by McGill https://www.ncbi.nlm.nih.gov/clinvar/variation/590772/

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.95.

PS3

From PAHvdb: R157T mutant has 5% PAH activity calculated as average of data obtained in eukaryotic cell systems. This data applies to variant R157N (PMID: 9450897), as comfirmed by Dr. Blau (email correspondence 2/2021 ("You are right. 5% belongs to p.Arg157Asn.")

c.470G>A;c.471A>C (R157N) in pcDNA3/human kidney cells A293 had 5% PAH enzyme activity PubMed:9450897

Approved on: 2021-02-14

Published on: 2021-05-14

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