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_000277.1:c.667A>T

CA16020834

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5100915b-09fa-4483-8f3a-364bf4973ce1

HGVS expressions

NM_000277.1:c.667A>T

NC_000012.12:g.102855175T>A

CM000674.2:g.102855175T>A

NC_000012.11:g.103248953T>A

CM000674.1:g.103248953T>A

NC_000012.10:g.101773083T>A

NG_008690.1:g.67428A>T

NG_008690.2:g.108236A>T

ENST00000553106.6:c.667A>T

ENST00000307000.7:c.652A>T

ENST00000549111.5:n.763A>T

ENST00000553106.5:c.667A>T

NM_000277.2:c.667A>T

NM_001354304.1:c.667A>T

NM_000277.3:c.667A>T

NM_001354304.2:c.667A>T

Uncertain Significance

PM3_Supporting PP4 PP3 PM2

PS3 PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.667A>T (p.Asn223Tyr) variant in PAH was reported with pathogenic variant c.165delT in a patient with PAH deficiency (242 μmol/L Phe) (PMID 18346471). 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 a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4, PM3_supporting.

PM3_Supporting

PMID 18346471: Table 1 listed c.165delT/p.N223Y (P 6 submitters) parental analysis not reported

PMID 18346471: Table 1 listed c.165delT/p.N223Y in one patient with Phe 242uM PubMed:18346471

PP4

PMID 18346471: Table 1 listed c.165delT/p.N223Y in one patient with Phe 242uM. BH4 deficiency not ruled out PMID 17096675: p.N223Y could be considered “mild”, because found in patients bearing a “severe” mutation on the second allele and showing a mild biochemical phenotype.

PMID 17096675: p.N223Y could be considered “mild”, because found in patients bearing a “severe” mutation on the second allele and showing a mild biochemical phenotype. PubMed:17096675

PMID 18346471: Table 1 listed c.165delT/p.N223Y in one patient with Phe 242uM PubMed:18346471

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.94

PM2

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

PS3

PMID 2182050: 48± 14% WT activity for p.N223Y PMID 18346471: 70% residual activity for p.N223Y

PMID 18346471: 70% residual activity for p.N223Y PubMed:18346471

PMID 2182050: 48± 14% WT activity for p.N223Y PubMed:21820508

PM5

p.Asn223Ile VUS

Approved on: 2021-01-15

Published on: 2022-04-16

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