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.833C>T (p.Thr278Ile)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229803

102863 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: dfa798e0-5398-4d65-8c83-93b9c35f7fd7

Approved on: 2022-03-05

Published on: 2022-04-16

HGVS expressions

NM_000277.1:c.833C>T

NM_000277.1(PAH):c.833C>T (p.Thr278Ile)

NC_000012.12:g.102852824G>A

CM000674.2:g.102852824G>A

NC_000012.11:g.103246602G>A

CM000674.1:g.103246602G>A

NC_000012.10:g.101770732G>A

NG_008690.1:g.69779C>T

NG_008690.2:g.110587C>T

ENST00000553106.6:c.833C>T

ENST00000307000.7:c.818C>T

ENST00000549247.6:n.592C>T

ENST00000553106.5:c.833C>T

NM_000277.2:c.833C>T

NM_001354304.1:c.833C>T

NM_000277.3:c.833C>T

NM_001354304.2:c.833C>T

NM_000277.3(PAH):c.833C>T (p.Thr278Ile)

Pathogenic

PS3_Supporting PP3 PP4_Moderate PM2 PM3_Strong

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.833C>T (p.Thr278Ile) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency ruled out), detected with pathogenic variants: R241C (PMID: 21307867); R241C, A259T (2 patients), R413P, Y356X (PMID: 15503242). Functional studies show a PAH enzyme activity of 1% compared to wild type (PMID: 9860305). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3, PS3_supporting.

PS3_Supporting

PAH residual activity of 1% PMID: 9860305. This PMID is approved for PS3_supp on PAH VCEP call 2/25/22

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster, REVEL=0.911

PP4_Moderate

>0.18mm PKU. Analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine. PMID: 21307867

PM2

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

PM3_Strong

Detected with R241C (ClinGen, P) parental analysis not reported PMID: 21307867; R241C (P), A259T (2 patients, P/LP), R413P (P), Y356X (P) parental analysis when available PMID: 15503242 (2.5 pts)

Curation History

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