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_000277.1(PAH):c.1184C>A (p.Ala395Asp)

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CA229374

102548 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 02b4987f-4fbd-49c2-a11f-21ac92e69ecc

Approved on: 2022-07-30

Published on: 2022-07-30

HGVS expressions

NM_000277.1:c.1184C>A

NM_000277.1(PAH):c.1184C>A (p.Ala395Asp)

NC_000012.12:g.102843661G>T

CM000674.2:g.102843661G>T

NC_000012.11:g.103237439G>T

CM000674.1:g.103237439G>T

NC_000012.10:g.101761569G>T

NG_008690.1:g.78942C>A

NG_008690.2:g.119750C>A

ENST00000553106.6:c.1184C>A

ENST00000307000.7:c.1169C>A

ENST00000549247.6:n.943C>A

ENST00000551114.2:n.846C>A

ENST00000553106.5:c.1184C>A

ENST00000635477.1:n.288C>A

ENST00000635528.1:n.699C>A

NM_000277.2:c.1184C>A

NM_001354304.1:c.1184C>A

NM_000277.3:c.1184C>A

NM_001354304.2:c.1184C>A

NM_000277.3(PAH):c.1184C>A (p.Ala395Asp)

Likely Pathogenic

PM5 PM2 PP4 PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1184C>A (p.Ala395Asp) variant in PAH was reported in 1 patient with PAH deficiency (>1200 μmol/L Phe) (PMID 16256386). This variant was found at an amino acid residue where p.Ala395Pro, a pathogenic missense variant has been seen before. Computational evidence for this missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease-causing (MutationTaster). This variant is absent from population databases ExAC, gnomAD, 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, PM5, PP3, PP4

PM5

p.Ala395Pro pathogenic 2 submitters

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PP4

PMID 16256386: p.Ala395Asp in one symptomatic patient (mental retardation between 6 months and 3 years old, classical PKU). PAH deficiency was diagnosed by conventional biochemical methods; classic PKU (Phe > 1200 umol/L).

PMID 16256386: Table 1. p.Ala395Asp in one symptomatic patient. PubMed:16256386

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster, REVEL=0.996

Curation History

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