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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CA16020973

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c902ca40-4683-4efb-bbf2-b066017fac3b

HGVS expressions

NM_001354304.2:c.1228T>A

NM_000277.1:c.1228T>A

NM_000277.2:c.1228T>A

NM_001354304.1:c.1228T>A

NM_000277.3:c.1228T>A

ENST00000307000.7:c.1213T>A

ENST00000551114.2:n.890T>A

ENST00000553106.5:c.1228T>A

ENST00000635477.1:n.332T>A

ENST00000635528.1:n.743T>A

NC_000012.12:g.102840487A>T

CM000674.2:g.102840487A>T

NC_000012.11:g.103234265A>T

CM000674.1:g.103234265A>T

NC_000012.10:g.101758395A>T

NG_008690.1:g.82116T>A

NG_008690.2:g.122924T>A

Likely Pathogenic

PP3 PP4 PM3 PM2

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The variant c.1228T>A (p.Phe410Ile) in PAH has been reported in 1 Danish patient with mild/moderate PKU (BH4 deficiency not excluded) (PMID: 26542770; PP4). This same patient carried this variant in trans with the previously reported c.1315+1G>A variant which has been reported as Pathogenic in ClinVar (PMID: 26542770; PM3). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.969 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4.

PP3

Variant predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.969.

PP4

PMID: 26542770 - F410I detected in 1 Danish patient with moderate/mild PKU (Phe = 600-1200umol/L), BH4 deficiency not excluded.

PubMed:26542770

PM3

PMID: 26542770 - F410I detected in trans in with c.1315+1G>A, reported as Pathogenic in ClinVar, confirmed in trans (VarID:576, 19 submitters) - 1.0 points.

PM2

Variant absent from population databases

PM5

Variant as same amino acid residue as NM_000277.3(PAH):c.1229T>C (p.Phe410Ser) (ClinVarID:102571, VUS, 2 submitters, not yet curated by ClinGen PAH VCEP) and c.1229T>G (p.Phe410Cys) (ClinVarID: 102572, no interpretation, 1 submitter) and has been curated by the ClinGen PAH VCEP as VUS.

Approved on: 2020-06-01

Published on: 2020-06-01

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