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_000277.3:c.998T>C

CA16020917

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 601f952f-355c-4c0c-92ee-2746e651b68e

Approved on: 2022-03-13

Published on: 2022-04-16

HGVS expressions

NM_000277.3:c.998T>C

NC_000012.12:g.102844403A>G

CM000674.2:g.102844403A>G

NC_000012.11:g.103238181A>G

CM000674.1:g.103238181A>G

NC_000012.10:g.101762311A>G

NG_008690.1:g.78200T>C

NG_008690.2:g.119008T>C

ENST00000553106.6:c.998T>C

ENST00000307000.7:c.983T>C

ENST00000549247.6:n.757T>C

ENST00000551114.2:n.660T>C

ENST00000553106.5:c.998T>C

ENST00000635477.1:n.102T>C

ENST00000635528.1:n.513T>C

NM_000277.1:c.998T>C

NM_000277.2:c.998T>C

NM_001354304.1:c.998T>C

NM_001354304.2:c.998T>C

Likely Pathogenic

PM3_Supporting PP4_Moderate PM5 PM2 PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.998T>C (p.Leu333Pro) variant in PAH has been reported in individuals with PAH deficiency, detected with p.Pro281Leu (Likely pathogenic by PAH VCEP variation ID: 589) with exclusion of BH4 deficiency (PMID: 19394257). In-vitro functional studies are unavailable. This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. A different pathogenic missense change at the same codon, p.Leu333Phe is pathogenic (by PAH VCEP). In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2, PM5, PM3_supporting.

PM3_Supporting

Detected with p.P281L (P/LP) in 2 patients, parental analysis not reported. 0.5 points

PP4_Moderate

Reported in a Croatian patient with PAH deficiency. BH4 deficiency was excluded in all patients by measuring urinary pterins and dried blood dihydropteridine reductase activity. PMID: 19394257

PM5

L333F is P by PAH VCEP

PM2

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

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.991

Curation History

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