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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.3(PAH):c.157C>T (p.Arg53Cys)

CA229445

102600 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a11b5555-6d5e-430a-80a6-ceb313b847c1

HGVS expressions

NM_000277.3:c.157C>T

NM_000277.3(PAH):c.157C>T (p.Arg53Cys)

ENST00000553106.6:c.157C>T

ENST00000307000.7:c.142C>T

ENST00000546844.1:c.157C>T

ENST00000548677.2:n.244C>T

ENST00000548928.1:n.79C>T

ENST00000549111.5:n.253C>T

ENST00000550978.6:n.141C>T

ENST00000551337.5:c.157C>T

ENST00000551988.5:n.246C>T

ENST00000553106.5:c.157C>T

ENST00000635500.1:n.125C>T

NM_000277.1:c.157C>T

NM_000277.2:c.157C>T

NM_001354304.1:c.157C>T

NM_001354304.2:c.157C>T

NC_000012.12:g.102912802G>A

CM000674.2:g.102912802G>A

NC_000012.11:g.103306580G>A

CM000674.1:g.103306580G>A

NC_000012.10:g.101830710G>A

NG_008690.1:g.9801C>T

NG_008690.2:g.50609C>T

Likely Pathogenic

PP4 PP3 PM3 PM2

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.157C>T (p.Arg53Cys) variant in PAH was reported in trans with pathogenic variant p.Arg158Gln in 1 patient with PAH deficiency (324 uMol/L Phe) (PMID: 28982351). This variant was found at an amino acid residue where p.Arg53His, a missense variant of uncertain significance, has been seen before. Computational evidence for this missense variant supports a deleterious effect (REVEL=0.766). This variant is found at an extremely low frequency in gnomAD and ExAC (MAF=0.00012), and absent from 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4.

PP4

detected in a patient with mHP (324 uMol/L Phe) Patients with BH4 cofactor deficiency were excluded by BH4 loading. PMID: 28982351

PP3

REVEL=0.766

PM3

detected in trans with p.Arg158Gln (P) 1.0 pts PMID: 28982351

PM2

extremely low frequency in gnomAD and ExAC (MAF=0.00012), absent from 1000 Genomes, ESP

PM5

R53H is classified as uncertain significance

Approved on: 2021-05-29

Published on: 2021-07-09

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