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_001354304.2:c.453T>A

CA16020793

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 54974578-304b-4ce9-bb26-5f6aa31359bb

Approved on: 2024-11-17

Published on: 2024-11-17

HGVS expressions

NM_001354304.2:c.453T>A

NC_000012.12:g.102866652A>T

CM000674.2:g.102866652A>T

NC_000012.11:g.103260430A>T

CM000674.1:g.103260430A>T

NC_000012.10:g.101784560A>T

NG_008690.1:g.55951T>A

NG_008690.2:g.96759T>A

ENST00000553106.6:c.453T>A

ENST00000307000.7:c.438T>A

ENST00000549111.5:n.549T>A

ENST00000551988.5:n.530+10810T>A

ENST00000553106.5:c.453T>A

NM_000277.1:c.453T>A

NM_000277.2:c.453T>A

NM_001354304.1:c.453T>A

NM_000277.3:c.453T>A

Likely Pathogenic

PP4_Moderate PP3_Strong PM3 PM2_Supporting

PM5

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 c.453T>A (p.Asp151Glu) variant in PAH has been reported in two patients with PAH deficiency: a patient with mild HPA, detected with pathogenic variant T380M (PMID: 11552030); and a patient with classic PKU, detected with pathogenic variant c.1066-11G>A (PMID: 23856132). This variant is absent from gnomAD. Multiple lines of computational evidence support a deleterious effect (REVEL=0.935). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PM3, PP3_strong, PP4_moderate.

PP4_Moderate

Reported in a patient with mild HPA (180-240 mmol/L), urinary pterins and erythrocyte DHPR were normal . PMID: 11552030

PP3_Strong

Predicted deleterious in SIFT, PP-2, MutationTaster, REVEL=0.935

PM3

T380M (P), parental analysis not reported PMID: 11552030; IVS10-11G>A, parental analysis not reported PMID: 23856132

PM2_Supporting

absent from gnomAD v4.1.0

PM5

D151G, H no interpretation in ClinVar, US by PAH VCEP

Curation History

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